Archives of Toxicology (2021) 95:1141–1159

https://doi.org/10.1007/s00204-021-02976-7

REVIEW ARTICLE

Carbon monoxide‑triggered health effects: the important role

of the inflammasome and its possible crosstalk with autophagy
and exosomes
Rong‑Jane Chen1 · Yu‑Hsuan Lee2   · Tzu‑Hao Chen3,4 · Yu‑Ying Chen3 · Ya‑Ling Yeh3 · Ching‑Ping Chang4 ·
Chien‑Cheng Huang3,5,6 · How‑Ran Guo3,7,8   · Ying‑Jan Wang3,9 

Received: 27 September 2020 / Accepted: 4 January 2021 / Published online: 8 February 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021

Abstract
Carbon monoxide (CO) has long been known as a “silent killer” because of its ability to bind hemoglobin (Hb), leading
to reduced oxygen carrying capacity of Hb, which is the main cause of CO poisoning (COP) in humans. Emerging stud-
ies suggest that mitochondria is a key target of CO action that can impact key biological processes, including apoptosis,
cellular proliferation, inflammation, and autophagy. Despite its toxicity at high concentrations, CO also exhibits cyto- and
tissue-protective effects at low concentrations in animal models of organ injury and disease. Specifically, CO modulates the
production of pro- or anti-inflammatory cytokines and mediators by regulating the NLRP3 inflammasome. Given that human
diseases are strongly associated with inflammation, a deep understanding of the exact mechanism is helpful for treatment.
Autophagic factors and inflammasomes interact in various situations, including inflammatory disease, and exosomes might
function as the bridge between the inflammasome and autophagy activation. Thus, the interplay among autophagy, mito-
chondrial dysfunction, exosomes, and the inflammasome may play pivotal roles in the health effects of CO. In this review,
we summarize the latest research on the beneficial and toxic effects of CO and their underlying mechanisms, focusing on the
important role of the inflammasome and its possible crosstalk with autophagy and exosomes. This knowledge may lead to
the development of new therapies for inflammation-related diseases and is essential for the development of new therapeutic
strategies and biomarkers of COP.

Keywords  Carbon monoxide · Mitochondria · NLRP3 inflammasome · Autophagy · Exosome

Abbreviations COHb Carboxyhemoglobin

CO Carbon monoxide ROS Reactive oxygen species
Hb Hemoglobin HO Heme oxygenase
BV Biliverdin
BR Bilirubin
Rong-Jane Chen and Yu-Hsuan Lee contributed equally to this IL-1β Interleukin-1β
work.

4
* How‑Ran Guo Department of Medical Research, Chi Mei Medical Center,
hrguo@mail.ncku.edu.tw Tainan, Taiwan
5
* Ying‑Jan Wang Department of Emergency Medicine, Chi Mei Medical
yjwang@mail.ncku.edu.tw Center, Tainan, Taiwan
6
1 Department of Senior Services, Southern Taiwan University
Department of Food Safety/Hygiene and Risk Management,
of Science and Technology, Tainan, Taiwan
College of Medicine, National Cheng Kung University,
7
Tainan, Taiwan Department of Occupational and Environmental Medicine,
2 National Cheng Kung University Hospital, Tainan, Taiwan
Department of Cosmeceutics, China Medical University,
8
Taichung, Taiwan Occupational Safety, Health and Medicine Research Center,
3 National Cheng Kung University Hospital, Tainan, Taiwan
Department of Environmental and Occupational Health,
9
College of Medicine, National Cheng Kung University, 138 Department of Medical Research, China Medical University
Sheng‑Li Road, Tainan 70428, Taiwan Hospital, China Medical University, Taichung, Taiwan

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Vol.:(0123456789)

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miRs MicroRNAs
COP Carbon monoxide poisoning
DM Diabetes mellitus
IRR Incidence rate ratios
CI Confidence interval
CK Creatine kinase
BNP Brain natriuretic peptide
FABP Fatty acid-binding protein
TLR4 Toll-like receptor 4
LPS Lipopolysaccharide
MAPK Mitogen-activated protein kinase
ASC Apoptosis-associated speck-like protein contain-
ing caspase-recruitment domain
NO Nitric oxide
mtROS Mitochondrial ROS
COPD Chronic obstruction pulmonary disease
Introduction: dark side and bright side of CO
Carbon monoxide (CO) is a colorless, tasteless, odorless
gas generated by incomplete combustion of carbon com-
pounds. Exposure to high concentrations of CO can cause
asphyxiation, severe neurocognitive effects, cardiac dysfunc-
tion, and death during accidental or occupational inhalation
(Von Burg 1999). In the United States, CO poisoning (COP)
affects approximately 50,000 people per year with mortality
rates ranging from 1 to 3% (Rose et al. 2017). The binding
affinity of CO to hemoglobin (Hb) is 250-fold greater than
that of oxygen, and so CO can reduce the oxygen carrying
capacity of Hb (Hall 2010). However, neither the clinical
severity of CO-poisoned patients nor the patients’ improve-
ment directly correlates with the blood carboxyhemoglobin
(COHb) level or COHb clearance (Hampson and Hauff
2008; Weaver et al. 2008). Thus, the toxic effects of CO
involve inhibition of oxygen delivery as well as binding to
other cellular heme-containing proteins, such as myoglo-
bin, mitochondrial cytochrome c oxidase, soluble guanylyl
cyclase, cytochrome p-450, inducible nitric oxide synthase
(NOS) and others (Borzelleca 2000; Rose et  al. 2017).
Thus, mitochondria may represent a key target of CO, and
exposure to CO results in changes in membrane potential,
generation of reactive oxygen species (ROS), release of pro-
apoptotic and pro-inflammatory mediators, and inhibition of
respiration at high concentrations (Ryter et al. 2018).
The dose determines the toxicity is a basic principle of
toxicology; thus, the same substance could act as a thera-
peutic at a lower dosage (Borzelleca 2000). In this regard,
when applied at low concentrations, CO has been used
as a gaseous therapeutic in experimental models of organ
injury and disease, as well as in conditions involving aber-
rant inflammatory or proliferative states (Ryter et al. 2006;
Ryter and Choi 2016). From these studies, accumulated data
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Archives of Toxicology (2021) 95:1141–1159
have emerged describing the physiological and cellular con-
sequences of CO exposure in vitro and in vivo as well as
the mechanisms responsible for these effects. In addition
to the effects of exogenous CO, a variety of biologic and
physiologic functions could be regulated by endogenous CO,
including vascular tone, mitochondrial homeostasis and bio-
genesis, neurotransmission, inflammation and programmed
cell death (Borzelleca 2000). Basically, CO can evolve
endogenously in living organisms as the result of enzymatic
heme degradation, which is catalyzed by the heme oxyge-
nase (HO) enzymes (Maines et al. 1986; Tenhunen et al.
1968). It has been well demonstrated that HO activity cata-
lyzes the oxidative cleavage of heme to biliverdin (BV), in
a reaction that liberates ferrous iron and CO. BV is further
enzymatically reduced to bilirubin (Keyse and Tyrrell 1989;
Maines et al. 1986; Tenhunen et al. 1970).
The success of CO as a therapeutic candidate in preclini-
cal models suggests its potential of further clinical appli-
cation to inflammatory and proliferative disorders, which
is currently under evaluation in clinical trials (Goebel and
Wollborn 2020; Kim and Choi 2018). Additional studies
are also needed to identify how discrete signaling targets of
CO are integrated in a context-specific fashion to coordinate
cyto- and tissue-protection.
The mechanisms by which HO-1 expression are associ-
ated with cyto- and tissue-protection have not been com-
pletely understood, but may involve the combined effects
of the removal of heme (a pro-oxidant iron-chelate) with
the enzymatic generation of CO and the generation of BV/
BR from heme catabolism (Ryter and Tyrrell 2000). Recent
studies have demonstrated that induction of HO-1 can reduce
interleukin-1β (IL-1β) maturation and downregulate inflam-
masome activation in a lung injury model (Luo et al. 2014).
Several molecular mechanisms and regulators have been
proposed for NLRP3 inflammasome activation, includ-
ing potassium efflux and calcium influx, lysosome desta-
bilization and rupture, mitochondrial ROS (mtROS), and
mitochondrial DNA damage. On the other hand, negative
regulators include autophagy, cytokines, CO, and miRNAs
(Jo et al. 2016; Rathinam and Fitzgerald 2016). A balance
between activation and inactivation of the NLRP3 inflam-
masome is critical for maintaining normal homeostasis and
physiological function (Mangan et al. 2018). Activation of
the NLRP3 inflammasome plays a pivotal role in the patho-
genesis of a variety of diseases such as atherosclerosis, myo-
cardial ischemia, ischemic stroke, hypertension, and diabe-
tes mellitus (DM) (Liu et al. 2020). Therefore, studies on
NLRP3 inflammasome, a core and important component of
innate immunity, may indicate new targets for the treatment
of various inflammatory diseases.
Autophagy is an evolutionarily conservative pathway
important to cellular homeostasis that is induced when
eukaryotic cells encounter various types of stimulation. It is
Archives of Toxicology (2021) 95:1141–1159 1143
involved in the process of recycling of damaged organelles
(e.g., mitochondria) and proteins as well as the destruction
of intracellular pathogens (Deretic 2011; Yin et al. 2016).
Autophagy and inflammasomes interact in many pathologi-
cal situations, including infectious disease, cancer, DM,
and neurodegeneration (Pu et al. 2019). Via crosstalk with
autophagic pathways, inflammasomes affect the effector
cells of innate and adaptive immunity during inflamma-
tory response (Rao and Eissa 2020). The interplay between
autophagy and inflammasome activation can be attributed
to multiple layers of molecular regulators, and the details
of such interplay remain largely unknown. Recent studies
have uncovered novel anti-inflammatory targets of HO-1/
CO, including regulation of autophagy and inflammasome
pathways. HO-1 may localize to mitochondria in response
to stress, whereas CO moderates mitochondrial dysfunction
and regulates autophagy and mitochondrial biogenesis. The
interplay among autophagy, mitochondrial dysfunction, and
the regulation of inflammation may make important contri-
butions to the protection afforded by HO-1/CO in cellular
and organ injury models (Ryter 2019). Interestingly, emerg-
ing studies suggest the critical involvement of microRNAs
(miRs) in the regulation of HO-1 gene expression either by
decreasing mRNA stability or by modulating the expres-
sion of upstream regulatory factors, such as Nrf2/Keap1
and Bach1 (Cheng et al. 2013). These findings indicate an
emerging complexity of HO-1 regulation and function that
may involve a network of miR-dependent regulatory events.
They also indicate that miRs may participate in the crosstalk
between inflammasomes and autophagy in physiological or
disease conditions (Pu et al. 2019).
Recent studies have revealed that exosomal and
autophagic pathways can be regulated by each other, and
the effects of this cross-regulation play important roles in
the occurrence and progression of various diseases (Lin
et al. 2019). Autophagy can regulate endosomal secretion
to form exosomes, which subsequently regulate autophagy
in a paracrine manner (Papandreou and Tavernarakis 2017).
In addition, growing evidence indicates that inflammasome
activity correlates with enhanced secretion of exosomes and
modulation of their protein cargo through the effector pro-
tease caspase-1 to alert and guide neighboring cells (Cypryk
et al. 2018). Accordingly, the present review summarizes the
most recent studies on the critical roles of exogenous CO and
the HO-1/CO system in inflammation and their underlying
mechanisms. We emphasize both organ injuries induced by
high-dose CO exposure and modulation of HO-1 expression
in cellular and organ protection, which implicate inflam-
mation as a key mediator of pathogenesis. In this regard,
studies on the NLRP3 inflammasome, the core mediator of
the inflammatory response, may indicate new targets for the
treatment of various inflammatory diseases. We also dis-
cuss currently available information about the interplay of
regulation that exists among inflammasome, autophagy, and
exosome. By analyzing these intriguing interconnections, we
hope to unveil the mechanisms involved in these processes
and provide potential therapeutic targets for certain diseases.
Updated knowledge regarding CO
intoxication
COP and major long‑term consequences
People suffering from COP manifest acute syndromes,
including headache, nausea, fatigue, dizziness, and chest
pain within a short period of time (Hampson et al. 2012).
Nonetheless, long term consequences such as neurologi-
cal disorders also need to be taken seriously. In addition,
Huang et al. (2014) reported that COP patients exhibited a
significantly increased risk of long-term mortality, which
is particularly high in the first month after COP and then
decreased slowly at 6 months to 1 year. Persistent neuro-
logical sequelae and delayed neurological sequelae are the
most common syndromes following COP, and both condi-
tions are triggered by white matter injury (Ning et al. 2020).
Chang et al. (2009) found that the fractional anisotropy value
of white matter on diffusion tensor imaging by CT or MRI
in the presence of acute brain lesions can predict delayed
neurological sequelae. Morphological changes in subcor-
tical structures and the pallidum have also been observed
after COP (Hsiao et al. 2004). However, Ozcan et al. (2016)
claimed that white matter lesions that progress to demyeli-
nation and result in neuropsychological sequelae could not
always be diagnosed by early CT or MRI in COP. Addition-
ally, neurocognitive deficits concomitant with depression,
anxiety, mental and psychiatric disorders, and violence con-
tribute to the increased risk for long-term mortality (Huang
et al. 2014). Apart from neurological disorder, COP has also
been demonstrated to cause long-term effects on the cardio-
vascular system, including myocardial dysfunction, ischemia
and infarction, arrhythmias, and cardiac arrest. Similarly, a
cohort study showed an increased long-term risk of major
adverse cardiovascular events in patients with COP (Wong
et al. 2017). It is believed that the direct damage of myocar-
dial mitochondria from tissue hypoxia by COP increases the
risk of developing myocardial diseases (Garg et al. 2018). In
addition, COP could damage pancreatic function and lead
to a higher risk of DM. Takahashi et al. (1982) found that
patients with 39.5% COHb manifested hyperamylasemia,
and the time course of amylase levels in COP patients is
similar to that in acute pancreatitis. Another cohort study
also demonstrated that COP is a potential risk factor for
developing subsequent DM, which is supported by the con-
cept that the brain and endocrine system are tightly linked.
Once the brain receives damage from COP, the endocrine
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system is likely to have problems producing or secreting
hormones; therefore, DM may develop (Huang et al. 2014;
Mimura et al. 1999).
Toxic mechanisms of CO: inflammation
and oxidative stress
It is widely believed that the mechanism of CO toxicity
involves rapid and strong binding of CO to Hb, thus decreas-
ing the ability of H­ bO2 to unload O ­ 2 and the subsequent
oxygen-carrying capacity of the blood. However, tissue
hypoxia may not be the only mechanism of the toxic effects.
Studies have indicated that CO may directly affect cellular
changes involving immunological, inflammatory, and oxi-
dative stress-triggered damage via a variety of mechanisms
including: (1) binding to intracellular proteins such as heme-
containing proteins, (2) nitric oxide generation and perox-
ynitrite production, (3) lipid peroxidation by neutrophils, (4)
mitochondrial oxidative stress, (5) apoptosis (programmed
cell death), (6) immune-mediated injury, and (7) delayed
inflammation (Hampson et al. 2012). In addition, Akyol
et al. (2014) dissected the involvement of a series of ROS
pathways in COP in distinct experimental studies. Accord-
ing to these studies, CO-induced damage is more widely
derived from inflammation and oxidative stress instead of
hypoxia. CO promotes the formation of ROS throughout
the body, possibly playing a critical role in the mechanism
of CO toxicity (Han et al. 2007; Roderique et al. 2015;
Tofighi et al. 2006). The burst in ROS may be accompanied
by damages attributable to free radicals in patients (Thom
1985). Indeed, it has been found that COP patients exhibited
increased serum total oxidative stress levels compared to
healthy controls (17.14 vs. 8.47 μmol H ­ 2O2 equivalent/L)
(Kavakli et al. 2011).
Target organs of CO after acute and chronic
exposures
Although cardiac and brain dysfunctions are recognized
as the major insults after COP, subsequent complications,
including endocrine disease, connective tissue disease, and
gastrointestinal disease, are exacerbated following COP.
Moreover, the respiratory system, the first target of CO
inhalation contact, may also be significantly affected during
COP. The following sections discuss the currently known
clinical or experimental animal studies with regard to CO
intoxication.
Cardiotoxicity following COP
CO has cardiotoxic effects, including myocardial injury
and subsequent cardiac dysfunction, which have been
described in clinical and experimental studies using
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Archives of Toxicology (2021) 95:1141–1159
in vivo and in vitro models (Gandini et al. 2001). Huang,
et al. (2019) found that patients with COP had an increased
risk of myocardial injury (incidence rate ratio: 1.45; 95%
confidence interval [CI] 1.06–1.98). Histological findings,
including focal areas of myocardial fiber degeneration with
vacuolization and mononuclear cell infiltration, have also
been reported. The main cardiotoxic effects of CO are as
follows: (1) left ventricular systolic and diastolic dysfunc-
tion, and wall motion abnormalities (Kim et al. 2020), (2)
ECG changes, including arrhythmia, disturbances of repo-
larization (e.g., T wave flattening and inversion), ischemic
changes (e.g., ST-segment depression or elevation), QT
interval prolongation, P wave elevation, QRS widening,
and R wave depression (Cetin et al. 2011; DeBias et al.
1976), and (3) myocardial injury (Huang et al. 2019). In
addition, a positive correlation was observed between
ambient CO levels and hospitalization for congestive heart
failure (Gandini et al. 2001).
Cerebral injuries following COP
Hypoxia has been suspected to be the major mechanism of
brain injury in patients with COP. However, animal studies
revealed that cerebral blood flow increases within minutes
during CO exposure initially and remains elevated until
loss of consciousness (Lo et al. 2007). This indicates that
hypoxia may not explain all the effects of COP. Persistent
neurological sequelae are noted in 46% of the COP survi-
vors. Delayed neurological sequelae, including cognitive and
personality changes, incontinence, psychosis, and Parkinson-
ism, are found in 10–30% of the survivors between 2 days
and 8 months following COP (Yogaratnam et al. 2011).
Brain injuries following COP as noted by imaging include
diffuse hypoxic-ischemic encephalopathy and focal cortical
injury; necrosis of the globus pallidus; injury to other basal
ganglia, thalamus, brainstem, and cerebellum; diffused brain
atrophy; and cerebral white matter demyelination (Lo et al.
2007). In addition to indirect effects through hypoxia, CO
can also affect the tissues in the brain directly. CO-induced
mitochondrial oxidative phosphorylation may also produce
ischemic and anoxic brain injuries, leading to cognitive
deficits in survivors. Furthermore, COP enhanced the pro-
duction of nitric oxide by vascular endothelium, which may
form oxygen free radicals at proximal sites. Overall, these
effects lead to mitochondrial dysfunction, capillary leakage,
leukocyte sequestration, and apoptosis in brain (Oh and Choi
2015). Moreover, brain ischemia can result from excitotox-
icity, acidosis, calcium influx and depolarization, oxidative
stress, nitrative stress, inflammation, and increases in the
levels of excitatory amino acids such as glutamine, lead-
ing to elevated nitrate levels and subsequent injury to the
cerebral cortex (Piantadosi et al. 1997; Rose et al. 2017).
Archives of Toxicology (2021) 95:1141–1159 1145
COP‑induced gastrointestinal injury
The gut-brain axis has already been used to explain the rela-
tionship between gut dysfunction and neuropsychiatric dys-
function (Singh et al. 2018a; b). Recent studies showed that
the incidence of gastrointestinal disease potentially increases
via autonomic dysfunction following brain injury (Katzen-
berger et al. 2015). Balzan et al. (1993) reported that intes-
tinal vasoconstriction due to COP made the gut much more
vulnerable to the hypoxic effects of CO than the brain and
heart. In addition, Gennari and Alexander (1996) reported
that the ­pO2 levels of bowel might be an important regu-
lator of gut barrier function. It is plausible that COP may
contribute to the increased risk of gastrointestinal disease
through hypoxia as well as immunological and inflammatory
damages (Weaver 2009). There have been case reports of
gastrointestinal diseases following CO exposure: a 24-year-
old female who suffered from intestinal and hepatic ischemia
(COHb: 34%) (Watson and Williams 1984), a 34-year-old
female who had diffuse colonic mural thickening and edema-
tous friable pale mucosa from rectum to distal sigmoid colon
(Weaver and Deru 2016), an 83-year-old female who devel-
oped ischemic colitis (COHb: 19.7%) (Duenas-Laita et al.
2008), and a 61-year-old female with upper gastrointestinal
bleeding (COHb: 33.6%) (Tekin et al. 2019). The frequency
of gastrointestinal bleeding is 103/100,000 per year in COP
patients. More importantly, there is solid evidence show-
ing increased intestinal permeability during gut damage via
tight junction disintegration (Arrieta et al. 2006). Numer-
ous studies have demonstrated intestinal damage following
COP via ischemia, inflammation, and gut junction disrup-
tion, implying that microbiota manifestation and distribution
may be an important feature during COP. On the other hand,
an experimental study in mice indicated that gastrointestinal
inflammation could induce anxiety-like behavior and altered
biomarkers related to brain dysfunction, which may be due
to inflammation in the brain (Bercik et al. 2010). It seems
that the brain-gut axis is bidirectional and involves more
than just the sensory input that positively influences mood
and behavior. Therefore, the brain-gut and HPA axes may
also play specific roles in the development of gut dysfunc-
tion following COP. However, the underlying mechanism
remains unclear.
Pulmonary diseases following CO inhalation
Inhalation is the main route of CO exposure. CO diffuses
from alveoli to lung capillaries and subsequently competes
with oxygen to bind Hb. Environmental CO comes from
various sources, including industrial fuel-burning, motor
vehicles, and cigarette smoke (5.9–17.4 mg CO/cigarette).
Studies on pulmonary diseases following acute COP are
limited. A case report demonstrated that a 15-year-old
child suffering from COP manifested acute cardiopulmo-
nary edema observed by chest X-ray (Wu et al. 2009).
Many environmental studies showed that ambient CO
may increase the risk of pulmonary disease (Losacco and
Perillo 2018). A study in the US reported that CO was
associated with emergency department visits for respira-
tory diseases overall and visits for asthma with a 3-day
lag (Slaughter et al. 2005). Another large study in China
reported that ambient CO contributed to pulmonary, car-
diovascular, genitourinary, gastrointestinal, and neuropsy-
chiatric diseases, especially in the warm seasons (Wang
et al. 2019). A meta-analysis of 87 eligible studies showed
that 42 of them observed a positive association between
short-term CO exposure from ambient air pollutant and
emergency department visits/hospitalization for asthma
with a pooled risk ratio of 1.045 (95% CI 1.029, 1.061;
I2 = 85.7%) associated with 1 mg/m3 increase and a popu-
lation attributable fraction of 4.3 (95% CI 2.8, 5.7) (Zheng
et al. 2015). Cigarette smoke is another common source
of CO exposure. Aside from the numerous toxic chemi-
cals in cigarette smoke, such as nicotine, tar, toluene, free
radicals, and pesticides, CO is a health hazard that should
not be overlooked. In smokers, COHb levels are generally
in the 3–5% range; for heavy smokers, the COHb levels
increase by approximately 20% (Hess 2017). In addition
to the high levels of COHb in serum, cigarette smokers
often exhibit pulmonary edema, barrier dysfunction, epi-
thelial and endothelial cells changes, neutrophil infiltra-
tion, and upregulation of IL-6 and CXCL-9 (Heijink et al.
2012; Zeglinski et al. 2019). In addition, wood smoke has
been found to disrupt barrier dysfunction in the alveolar
epithelial cells via the mitogen-activated protein kinase
(MAPK) signaling pathway (Zeglinski et al. 2019). These
phenomena were directly involved in increasing systemic
pulmonary capillary permeability after CO exposure.
Although CO is a fatal toxin with some potential proper-
ties that require verification, few studies have explored
the underlying mechanisms through which CO leading to
pulmonary dysfunction. Thus, pulmonary diseases caused
by COP should be studied more extensively.
In summary, studies have revealed that cognitive seque-
lae are not the only complications of COP. In addition to
the brain, other organs affected by COP include the heart,
lung, and intestines, as noted in clinical reports and ani-
mal experiments (Fig. 1). Whether the injured tissue can
transmit impaired signals to other locations or transmit
the “eat me” signal to immune cells to reinforce the repair
system is an important issue that should be further inves-
tigated. Another issue of concern is whether organ-organ
communication is impaired by neuroendocrine or hormone
disruption after COP.
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Fig. 1  Schematic diagram of multiorgan damages induced by carbon
monoxide poisoning (COP). Several organs manifest deficits after
COP. The main target organs that are most often discussed in the cur-
rent literature include brain, heart, lung, and bowel (included intes-
tine and colon). In the brain, the most commonsyndrome is delayed
neurological sequelae combining cognitive and personality disorders.
These patients also exhibit necrosis and/or apoptosis in specific brain
regions, such as the globus pallidus, thalamus, brainstem, cerebellum,
and basal ganglia. COP-induced hypoxia–ischemia damage causes
encephalopathy. The mechanism involves CO directly binding to
cytochrome c in mitochondria, thereby generating ROS, and reducing
ATP production. Fewer studies have assessed the underlying molecu-
lar mechanism of damages to the lung after COP; nevertheless, a few
case reports indicated that COP patients exhibit acute cardiopulmo-
nary edema. Prospective/retrospective studies using large data also
demonstrated that ambient CO may increase the risk of pulmonary
diseases. Moreover, cigarette smokers have higher COHb blood levels
General biomarkers in COP
Many investigators have searched for biomarkers that can
predict complications and severity following COP. Some
biomarkers, including creatine kinase (CK), CK-MB, tro-
ponins, natriuretic peptides (NT-proANP, NT-proBNP, etc.),
and S100B, have been used to predict the toxicity of CO
to the brain or heart (Gawlikowski et al. 2014). The most
frequently used enzymes are CK-MB and troponin I. Eren-
ler et al. (2013) reported that troponin I and CK-MB lev-
els increased to 0.2 ng/mL (range 0–17.9 ng/mL; reference
value, 0.0–1.0 ng/mL) and 3.1 ng/mL (range 0.2–167 ng/
mL; reference value, 0–3.2 ng/mL), respectively, in COP
patients. Lippi et al. (2012) also found that the troponin I
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Archives of Toxicology (2021) 95:1141–1159
with immune cell infiltration and lung integrity disruption, which is
medicated by ERK pathway activation. As to the heart, a variety of
clinical syndromes of COP result in heart failure, including cardiac
contractility exacerbation and myocardial injury. ECG abnormali-
ties have been observed following COP. In the bowel, ischemia and
hypoxia accompanied with inflammation are noted, and three clini-
cal cases also revealed gut damage, even bleeding, after COP. Once
inflamed, intestinal integrity is disrupted, and enteric microflora and
their metabolites may enter the vascular or lymphatic system. In
summary, hypoxia–ischemia, ROS generation, immune cell relative
responses, cell apoptosis, and necrosis are commonly observed after
COP. The crosslink between target organs may influence each other
through distinct pathways. Crosstalk between hormones and neuroen-
docrine factors via the hypothalamus-pituitary gland-adrenal gland
(H–P–A) or hypothalamus-pituitary gland-thyroid gland (H–P–T)
axis may play a vital role in organ-organ communication
level increased (> 0.1 mg/L) in 30% of patients with COP
and was positively correlated with the level of COHb.
Endogenous natriuretic peptides, such as brain natriuretic
peptide (BNP), are cardiac hormones that act as markers
of left ventricle function. Because there are positive cor-
relations between BNP and COHb and between COHb and
CK, BNP may be used as an early marker of cardiotoxicity
in COP (Davutoglu et al. 2006). Fatty acid-binding protein
(FABP), which is found in myocyte cytoplasm and released
from injured myocardium, has been reported as a biomarker
of COP. Erenler et al. (2013) reported that serum heart-type
FABP increased in patients with severe COP. They also
reported positive correlations between heart-type FABP
and the levels of COHb, troponin I, and CK-MB. However,
Archives of Toxicology (2021) 95:1141–1159 1147
these candidate biomarkers also increased in other brain
and heart diseases, such as encephalopathy and ischemic/
hemorrhage shock, not specifically for COP. Another major
problem associated with these candidate COP biomarkers is
that they typically only change in the first 12–24 h after CO
exposure and return to normal levels after 24 h (Kim et al.
2016). Therefore, they are not suitable for predicting long-
term sequelae following COP.
Therapeutic potential of CO and its
underlying mechanisms
The overall beneficial effects and mechanisms
triggered by CO
Although inhalation of high concentrations of CO may cause
certain toxic effects, studies have discovered that CO has
certain beneficial effects and confirmed that CO exhibits
potential benefits in medical applications. Initially, some
clinical data revealed increased levels of CO in diseased
patients, and the induction of HO-1 under stress conditions
strongly suggested that endogenously produced CO has
beneficial or therapeutic effects (Romao et al. 2012). This
hypothesis was later confirmed in various animal models
of human diseases using inhaled CO (Romao et al. 2012).
For more convenient use of CO in medical applications,
CO-releasing molecules (CORMs) have been developed as
a new strategy that can provide CO in therapeutic applica-
tions without significantly affecting COHb levels (Ismailova
et al. 2018). CORMs can release CO and mimic the medi-
cal effects of gaseous CO in animals (Romao et al. 2012).
Inhalation-based and CORM-based exogenous CO can be
used to induce HO-1 to metabolize heme into BV, ­Fe2+ and
CO (Duvigneau et al. 2019), and induction of HO-1 gene
expression by genetic or pharmacological (e.g., heme deriva-
tives and anesthetics) approaches represent new strategies to
induce CO production (Abraham et al. 2016; Levy 2016).
CO is recognized as an important signal messenger that
can affect multiple pathways. Currently, the best-known
therapeutic effects of CO are classified into three catego-
ries: (1) Anti-inflammatory effects that inhibit the produc-
tion of pro-inflammatory cytokines (e.g., IL-6 and TNF-α)
and increase anti-inflammatory cytokines (e.g., IL-10) via
regulation of MAPK cascades, such as ERK1/2, JNK and
p38 pathways (Otterbein et al. 2000). CO also activates
Stat1/Stat3, PPAR-γ, and HIF-1α to inhibit the TGF-β and
Egr-1 genes (Hoetzel et al. 2008). Egr-1 is considered to be
a multi-effect inflammatory trans-activator, regulating hun-
dreds of target genes, including IL-1β, IL-6, TNF-α, and
ICAM-1. In addition, CO inactivates Toll-like receptor 4
(TLR4) by downregulating NADPH oxidase activity. TLR4
induces the expression of inflammatory response-related
genes. These effects collectively contribute to the anti-
inflammatory effect of CO (Knauert et al. 2013). (2) Anti-
apoptotic reactions that inhibit the cellular apoptosis path-
way in mitochondria (Kim and Choi 2018). CO activates
the PI3K/Akt pathway to inhibit GSK-3β activity, which is
involved in numerous apoptotic signaling pathways (Kim
and Choi 2018; Kim et al. 2013; Zhang et al. 2005). (3)
Vasodilatory effects that regulate blood vessel smooth mus-
cle tone via activation of the sGC/cGMP pathway (Kim and
Choi 2018). After activation of sGC, the subsequent increase
in cGMP in smooth muscle cells leads to PKG activation,
induces the reuptake of ­Ca2+ by the sarcoplasmic reticulum,
and leads to reduced intracellular ­[Ca2+] and smooth muscle
relaxation (Kim and Choi 2018).
In recent decades, many researchers have tried to use the
unique characteristics of CO to treat diseases. Most stud-
ies indicate that endogenous CO and exogenous CO gas
inhaled at doses such that the oxygen-carrying capacity of
hemoglobin is not severely compromised (COHb < 20%) can
provide protective and beneficial effects against organ injury,
inflammation disease, ischemia–reperfusion injury, and car-
diovascular disease (Bauer and Pannen 2009).
Application of CO in human diseases
In 1999, a model using hyperoxia-induced lung injury rats
showed improved survival and alleviated lung injury after
exposure to low concentrations of CO (Otterbein et  al.
1999). The study is probably the first in vivo evidence dem-
onstrating that low-dose gaseous CO exhibits therapeutic
potential. CO exposure inhibits pro-inflammatory cytokines
involved in the MKK3/p38 MAPK pathway to achieve anti-
inflammatory and anti-apoptotic effects (Bauer and Pannen
2009). In addition, other types of lung injury (such as acute
lung injury, asthma, and acute respiratory distress syndrome)
have been assessed, and the protective effect of inhaled CO
has been confirmed (Bauer and Pannen 2009; Foresti et al.
2008; Ismailova et al. 2018).
Given its anti-inflammatory effect, CO exhibits the poten-
tial as a treatment for inflammation-related diseases. For
example, systemic inflammatory response syndrome is an
inflammatory condition that affects the entire body. Inflam-
matory responses and organ damages induced by lipopoly-
saccharide (LPS) are models of systemic inflammation that
have been used in multiple studies to verify the therapeutic
effect of CO (Bauer and Pannen 2009; Foresti et al. 2008;
Ismailova et al. 2018; Nakahira and Choi 2015). In pigs and
rodents treated with LPS, inhaled CO can reduce the LPS-
induced cytokine responses and improve long-term survival
through antioxidant, anti-inflammatory, and anti-apoptotic
effects (Bauer and Pannen 2009). Another study also showed
that CORM-2 suppressed the thioredoxin-interacting pro-
tein/NLRP3 inflammasome pathway and protected against
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LPS-induced lung injury (Jiang et al. 2016). Wang et al.
(2015) provided evidence that CORM-2 protected against
sepsis-induced acute kidney injury and reduced TNF-α and
IL-1β levels, oxidative stress, and NLRP3 inflammasome
activation.
Regarding ischemia–reperfusion injury, including
transplantation, CO is considered to be a very promising
treatment given its anti-inflammatory and anti-apoptotic
effects (Cheng and Rong 2017; Ismailova et al. 2018). In
experimental models of heart transplantation, CO reduced
ischemia–reperfusion injury and cardiac rejection of mouse
to rat cardiac transplants via anti-apoptotic, anti-inflamma-
tory, and vasodilatory mechanisms as well as suppression
of platelet aggregation and fibrinolysis (Bauer and Pannen
2009; Soni et al. 2012). In the recipient, low-dose CO inha-
lation after transplantation effectively ameliorated heart
allograft rejection via downregulation of pro-inflammatory
mediators (Cheng and Rong 2017).
Additionally, CO has an inhibitory effect on the initia-
tion and progression of heart and blood vessel diseases. CO-
induced vasodilation ameliorates acute coronary syndrome
by expanding coronary arteries, especially in the case of
angina pectoris, and reducing myocardial cell death through
anti-apoptotic and anti-inflammatory properties (Kim and
Choi 2018). CO also stabilizes blood pressure in patients
with hypertension by regulating vascular tone. In patients
with pulmonary hypertension and heart failure, CO relieves
pressure in the pulmonary and systemic vasculature (Kim
and Choi 2018). CO inhibits the proliferation of smooth
muscle cells in coronary arteries to avoid the formation of
coronary atherosclerosis and prevents the occurrence of
coronary obstructive diseases (Kim and Choi 2018).
In summary, the positive effects of CO are evident. To
date, several clinical trials have been conducted to evalu-
ate the therapeutic effects of exogenous CO, e.g., treatment
of acute respiratory distress syndrome caused by sepsis,
reduction of postoperative ileus after colon resection, and
improvement of chronic inflammation in chronic obstructive
pulmonary disease (COPD) (Kim and Choi 2018). However,
it must be noted that due to the dose-dependent dual nature
of CO, when CO and CORM are used for therapeutic pur-
poses, it is important to continuously monitor CO concen-
trations and establish an accurate therapeutic range for safe
treatment (Ismailova et al. 2018).
Application of CO in cancer therapy
The dual role of CO transforms it from a toxic substance
to a therapeutic agent, and more interestingly, studies have
demonstrated that CO has anti-cancer effects. In contrast
to the mechanism triggered by CO to treat diseases, such
as inflammation, the application of CO in anti-cancer treat-
ment is based on other mechanisms. Cancer cells can change
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Archives of Toxicology (2021) 95:1141–1159
their metabolism in the context of processed glucose and
other energy sources to promote survival and proliferation
(Schwartz et al. 2017). This change in metabolism is called
the Warburg effect. CO can induce the anti-Warburg effect by
forcing cancer cells to increase respiration, quickly fueling
the cancer cell’s bioenergy and eventually leading to meta-
bolic failure (Wegiel et al. 2013). As the role of the HO-1/
CO system in angiogenesis and metabolism in tumor growth
has been clarified, CO has also started to be perceived as an
anti-tumor therapy strategy (Loboda et al. 2015).
Specifically, inhibition of tumor angiogenesis can prevent
tumor growth and even to cause tumor regression in various
experimental models. CO influences the tumor angiogen-
esis response that depends on the production of cGMP and
the modulation of MAPK pathways (Pae et al. 2008). In
addition, CO is involved in the angiogenic pathways driven
by the two major angiogenic mediators, VEGF and stromal
cell-derived factor-1, and improves endothelial cell viability
and reactions (Dulak et al. 2008; Kourti et al. 2019; Lv et al.
2019).
CO is also involved in the modulation of immune reac-
tions. The effects of CO on tumor stroma and reprogram-
ming of macrophages towards the anti-tumoral phenotype
are mediated by ROS-dependent activation of the MAPK/
Erk1/2-c-myc pathway and Notch 1-dependent negative
feedback on the metabolic enzyme HO-1 (Nemeth et al.
2016). Furthermore, HO-1 and CO regulate T cell responses
by inhibiting dendritic cell function. CO pretreatment mark-
edly suppressed intracellular ROS generation and the activi-
ties of NADPH oxidase and mitochondrial complexes I–IV
in T cells after stimulation. Moreover, increasing intracel-
lular ROS via hydrogen peroxide supplementation largely
reversed the inhibitory effect of CO on T cell proliferation.
The inhibitory effects of CO on both cell proliferation and
intracellular ROS production were also shown in a T cell
proliferation model involving stimulation by allogeneic den-
dritic cells. In addition, CO treatment significantly inhibited
T cell activation in vivo (Yan et al. 2020).
Various studies have explored the therapeutic effects of
CO in various types of cancer, including breast cancer, non-
small cell lung carcinoma, pancreatic cancer, and prostate
cancer (Loboda et al. 2015). In this context, CO inhibited
ERK/AP-1 activation; HSP90 client protein activity, such
as AKT, ERα and cyclin D1; and the expression of cyclin
D1, CDK4, and hTERT. CO blocked the growth of breast
cancer cells independently of p53, which was destabilized,
ubiquitinated, and degraded in response to CO (Lee et al.
2014). CO also significantly inhibits proliferation and inva-
sion and induces apoptosis in prostate cancer cells. LKB1
expression is upregulated after CO treatment, which also
increases p-AMPK levels and decreases p-mTOR. Further-
more, LKB1 knockdown could weaken the effect of CO on
prostate cancer cells (Yan et al. 2018).
Archives of Toxicology (2021) 95:1141–1159 1149
Overall, the anti-proliferative properties of CO may
indeed have chemotherapeutic potential against certain can-
cers. In controlled doses, CO not only mimicked the effects
of chemotherapy agents by blocking proliferation of cancer
cells, but also amplified the toxic effects of the chemother-
apy drugs to accelerate cancer cell death (Li et al. 2019;
Loboda et al. 2015; Wegiel et al. 2013). More importantly,
a common side effect of cancer treatment is the injury of
normal tissues by chemotherapy agents, and CO can pro-
tect normal tissues while fighting cancer cells (Wegiel et al.
2013). This finding adds to the feasibility of using CO for
anti-cancer treatment (Fig. 2).
Fig. 2  Protective effects and potential therapeutic applications of
carbon monoxide. CO is a heme ligand that can bind to and poten-
tially modulate the cellular activity several heme-containing proteins.
Regarding anti-cancer effects, many studies have discussed the thera-
peutic effects of CO on various cancer types. HO-1 expression inhib-
its cancer cell proliferation. This effect might be mediated by CO,
which inhibits ERK/AP-1 activation and HSP90 client protein activ-
ity, such as cyclin D1, CDK, and hTERT. Inhibition of p53 protein in
response to CO treatment was also reported. CO can also modulate
Role of the HO‑1/CO system
in inflammasome regulation
Detoxification effects of the heme oxygenase family
and interacting regulators
HO is the primary and rate-determining enzyme in the heme
catabolic pathway, which plays a crucial role in protecting
cells from heme-induced oxidative stimuli. In general, HO
breaks down the heme group and produces endogenous
CO to ameliorate oxidative stress and the inflammatory
response, including regulation of the inflammasome system
(Gomperts et al. 2017; Liu et al. 2019; Waza et al. 2018;
Wu et al. 2019). There are three distinct isoforms of HO:
HO-1, HO-2, and HO-3 (Gáll et al. 2019; Waza et al. 2018).
Among them, HO-1 is the focus of most research, because
its expression is enhanced under various pathophysiologi-
cal conditions (Waza et al. 2018). HO-1 can be induced by
a wide variety of stimuli, such as hypoxia, oxidative stress,
cytokines, LPS, and heavy metals in biological systems
inflammatory responses by several established mechanisms, including
the p38 MAPK-dependent downregulation of inflammation and apop-
tosis effects. CO can activate PPAR-γ to inhibit Egr-1 gene to down-
regulate inflammation. Recent studies also indicate that low-level CO
exposure affects mitochondria inhibition and can alter the autophagy
pathway induction. Activated autophagy flux might downregulate the
NLRP3 inflammasome and pyroptosis pathway in response to pro-
inflammatory stimuli
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(Waza et al. 2018). The alterations in the HO-1 level are
associated with the pathogenesis of some age-dependent
disorders, including neurodegeneration, inflammatory dis-
orders, and cancer (Wegiel et al. 2014). Since HO-1 induc-
tion is widely recognized as a mechanism used by cells to
neutralize stress conditions, the induction of this powerful
enzyme becomes a therapeutic strategy against different dis-
eases, arising as a result of inappropriate immune response
and oxidative dysregulation. Particularly, the identifica-
tion of noncytotoxic HO-1 inducers may represent a novel
approach to cope against various oxidative and inflammatory
responses (Son et al. 2013).
Earlier studies indicate that different HO-1 inducers acti-
vate diverse protein phosphorylation-dependent signaling
pathways that ultimately regulate HO-1 gene expression by
activating a wide variety of transcription factors, such as
PI3K/Akt, MAPK, and Nrf2 (Chen et al. 2013). For exam-
ple, Hemin is the substrate and a well-known inducer of
HO-1. A recent study showed that it provided protection
against lead neurotoxicity by HO-1/CO activation (Ye et al.
2018). Multiple functions of HO-1 have been confirmed in
biological systems, and its protective effects could involve
its ability to degrade heme (Gáll et al. 2019; Waza et al.
2018), whereby the byproducts of heme degradation (mostly
CO and BR) mediate its cytoprotective effects. Interestingly,
evidence indicates that extensive exogenous CO can also
disrupt the HO-1/CO system. Acute COP in rats reduced
HO enzyme activity, whereas HO-1 protein expression
was consistently upregulated in a time-dependent manner.
Endogenous CO produced by activated HO-1 is increased in
the hippocampus of the rat brain, which is potentially associ-
ated with brain injury following COP (Guan et al. 2011). In
general conditions, normal brain tissue exhibits basal expres-
sion of HO-1 and Nrf-2 proteins; however, COP activates
the HO-1/Nrf-2 pathway and induces oxidative stress, caus-
ing brain lesions. Various drugs can be used to upregulate
the expression of HO-1 and Nrf-2, including those that may
increase endogenous biological CO, inhibit oxidative stress
and apoptosis, or activate the Keap1-Nrf/ARE pathway to
improve neurophysiologic changes following COP (Guan
et al. 2009; Li et al. 2016).
The HO‑1/CO system exerts cytoprotective effects
by regulating the inflammasome system
CO exposure rapidly increases brain cytosolic heme levels
through three mechanisms: (1) alteration in heme synthesis, a
process that is regulated by CO; (2) release of heme from dam-
aged cellular proteins; and (3) disturbance in mitochondrial
heme storage by CO (Rose et al. 2017) (Fig. 3). In addition
to these three major mechanisms, research suggests a poten-
tial regulatory role of HO-1/CO in the inflammasome system,
especially the NLRP3 inflammasome. The inflammasome
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Archives of Toxicology (2021) 95:1141–1159
consists of pattern recognition receptors, the adapter protein,
apoptosis-associated speck-like protein containing caspase-
recruitment domain (ASC), and the protease caspase-1.
NLRP3 (NACHT, LRR and PYD domains-containing pro-
tein 3) is an intracellular recognition receptor that can detect a
broad range of microbial factors, endogenous danger signals,
and environmental irritants, resulting in the formation and acti-
vation of the NLRP3 inflammasome (Swanson et al. 2019).
Assembly of the NLRP3 inflammasome leads to release of
caspase 1, maturation of pro-inflammatory cytokines IL-1β
and IL-18, and gasdermin D-mediated pyroptotic cell death
(Shao et al. 2015). In innate immune activation, the inflamma-
some plays a critical role by activating cytosolic multiprotein
complexes that induce inflammatory cytokine production after
sensing invading pathogens (Shao et al. 2015). Recent studies
demonstrated that heme preconditioning of HO-1 induction
reduced IL-1β maturation and downregulated inflammasome
activation in a model of sepsis-associated lung injury (Luo
et al. 2014; Ryter 2019).
The actual underlying mechanism of the anti-inflammatory
properties of HO-1 in CO exposure is not fully understood.
However, the signaling action of CO together with the anti-
oxidant properties of BV/BR and iron sequestration by fer-
ritin contributes to the amelioration of inflammation (Loboda
et al. 2016). HO-1 expression inhibits ovalbumin-induced air-
way inflammation in asthma via downregulation of NLRP3-
dependent regulation of retinoid-X receptor (RXRa/b/g) acti-
vation (Lv et al. 2018). Moreover, in an NLRP3 inflammasome
activation model, the application of CO gas inhibits activation
of caspase-1 and secretion of IL-1β and IL-18 in bone marrow-
derived macrophages in response to LPS and ATP treatment
(Cronje et al. 2004; Lee et al. 2017a). Although the precise
mechanisms still require further clarification, HO-1 and CO
exhibit the potential of functioning as novel regulators of the
NLRP3 inflammasome and secretion of IL-1β and IL-18 in
inflammatory conditions (Chen et al. 2013).
CO exposure at different concentrations exerts both anti-
inflammation and inflammation effects via cellular responses.
Exposure to high concentrations of CO might activate the
inflammation through the NLRP3 inflammasome by affect-
ing mitochondria and upregulating mtROS, thereby inducing
the HO-1 system to alleviate the inflammation. In contrast, at
low concentrations, CO acts as an efficient anti-inflammatory
agent through inducing the HO-1 system.
Archives of Toxicology (2021) 95:1141–1159 1151
Fig. 3  Mitochondrial effects of CO poisoning. Under normal condi-
tions, hemoglobin (Hb) binds oxygen (­O2) and delivers it to periph-
eral tissues. In the cytosol, mitochondria produce energy by con-
suming oxygen. Complex IV receives the electron transferred by
cytochrome c. Electrons are first transferred to cytochrome c oxidase
(COX) subunit 1 (­Cua). The electron reduces O ­ 2 at subunit 2 (Cyta3
and ­Cub), forming water and transporting a proton (­H+) through the
mitochondrial intermembrane space. Upon exposure to CO, CO com-
The possible role of CO in the interplay
among the inflammasome, autophagy
and exosomes
Crosstalk between autophagy and inflammasome
triggered by CO
Growing evidence has shown that autophagy plays important
roles in various biological processes. Autophagy is induced
at a low frequency under steady-state conditions and con-
tributes to cellular homeostasis by promoting the turnover
of organelles, such as mitochondria (Dikic and Elazar 2018).
CO exposure might activate autophagy through mtROS for-
mation (Lee et al. 2011). It has been demonstrated that CO
exposure time-dependently increased the expression and
activation of an autophagic protein, microtubule-associated
protein-1 light chain-3B, in mouse lung and in both cultured
petitively binds to Hb with O­ 2, reducing its total O
­ 2 carrying capacity
and affecting cytochrome proteins. This action causes the following:
(1) inhibition of the reduction of ­O2 to water (the end destination of
electrons in the electron transport chain), (2) inhibition of the transfer
of ­H+ into the intermembrane space, shutting down ATP generation
through ATP synthase, and (3) accumulation of electrons entering the
electron transport chain through complexes I and III, which generates
ROS and leads to deleterious effects
human alveolar (A549) and human bronchial epithelial cells
(Lee et al. 2011). Formation of mtROS might be an activa-
tion signal of the inflammasome (Shao et al. 2015). Given
that these two pathways exhibit distinct effects and occasion-
ally crosstalk, we argue that CO-mediated cellular responses
could be mediated by the interaction between autophagy and
the inflammasome.
Many studies have indicated that autophagy inhibits
inflammasome activation, thereby inhibiting inflammatory
responses and reducing inflammatory injuries in a variety
of diseases (Chen et al. 2016). The mechanism through
which autophagy inhibits NLRP3 inflammasome could be
related to the reduction of NLRP3 components (NLRP3,
ASC), sequestration and degradation of pro-IL-1β, and the
clearance of mtROS (Cao et al. 2019; Liu et al. 2018). A
recent study indicated that immunity-related GTPase M,
which belongs to a family of interferon-inducible GTPases
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involved in resistance to intracellular pathogens, could medi-
ate selective autophagic degradation of NLRP3 and ASC
to protect gut inflammation in a Crohn’s disease model
(Mehto et al. 2019). Moreover, autophagy was also reported
to limit inflammation by downregulating caspase 1-depend-
ent inflammasome cleavage of pro-IL-1β to the active form
(Ilyas et al. 2016). HO-1 generated CO is required for the
induction of autophagy and killing of pathogens resid-
ing in macrophages in response to immunomodulation by
interferon-γ (Singh et al. 2018a, b). In addition, the accu-
mulation of higher concentrations of mitochondrial damage-
induced mtROS in response to autophagy/mitophagy inhibi-
tion was associated with NLRP3 inflammasome activation
and the release of IL-1β by macrophages (Rocha et al. 2020).
Notably, a recent study indicated a novel interaction pathway
among actin assembly, autophagy, and the inflammasome
activation (Lee et al. 2017a, b). Lee et al. (2017a, b) showed
that deficiency of Wiskott-Aldrich syndrome protein, which
signals to the actin cytoskeleton and causes defective bac-
terial clearance, excessive inflammasome activation, and
host cell death, plays a crucial role in impaired autophagic
p62/LC3 recruitment and defective formation of canonical
autophagosomes. Taken together, autophagy is generally
recognized as a negative feedback regulator of inflammation.
Thus, in the context of autophagic dysfunction, damaged
mitochondria, proteins, and ROS can be accumulated and
then trigger the novel signaling pathways described above,
which may be induced to promote inflammasome activation.
A mutual relationship between autophagy and the inflam-
masome has been reported recently. Although autophagy
was assumed to act as a negative regulator of the NLRP3
inflammasome, the NLRP3 inflammasome also positively
regulates the activation of autophagy. Deng et al. (2016)
showed that, probably for the first time, Pseudomonas
aeruginosa infection induced the assembly of the NLRP3
inflammasome and secretion of caspase 1 and IL-1β. Silenc-
ing of the NLRP3 inflammasome impaired the elimination
of P. aeruginosa in macrophages by reducing the level of
IL-1β/IL-18 secretion and autophagy (Deng et al. 2016).
The finding is consistent with a previous study indicat-
ing that activation of caspase 1 could promote adaptive
responses to oxidative stress and increase autophagic
influx by upregulating Beclin 1 (Sun et al. 2013). Similar
to the abovementioned study, a study using human mono-
cytic cell line (THP-1)-derived macrophages showed that
activation of the NLRP3 inflammasome may serve as an
immune defense strategy against T. pallidum and mycobac-
teria infection through modulation of autophagy (Xu et al.
2020). In addition, it was found that ncRNAs (including
lincRNA) played an important role in the crosstalk between
the NLRP3 inflammasome and autophagy (Xue et al. 2019).
It is also reported that lincRNA-Cox2 could bind to NF-κB
p65 and promote its nuclear translocation and transcription,
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Archives of Toxicology (2021) 95:1141–1159
modulating the expression of NLRP3 and ASC (Xue et al.
2019). Taken together, the crosstalk between the inflam-
masome and autophagy is complex and bidirectional with
context-dependent features. The relationship and underlying
mechanisms between autophagy and the inflammasome in
response to CO exposure need to be further investigated.
Exosomes exhibit interplay
with both the inflammasome and autophagy
In addition to its well-known role in processing pro-inflam-
matory cytokines, the inflammasome can also serve as a
universal regulator of protein secretion, which allows the
release of various proteins from cells exposed to danger
signals to alert and guide neighboring cells. These pro-
teins are mostly segregated in membrane-enclosed com-
partment and secreted in nano-sized extracellular vesicles
named exosomes (Cypryk et al. 2018). The impact of this
type of intercellular communication in the clinical setting
has recently been recognized. For instance, exosomes iso-
lated from body fluids of patients have been proposed to
serve as disease or early diagnosis biomarkers of inflamma-
tory-related diseases, such as atherosclerosis, Alzheimer’s
disease, and rheumatoid arthritis (Cypryk et al. 2018). It
has been shown that the immune response-related pro-
teins and signaling pathways were specifically enriched in
inflammasome-derived exosomes and directly activated the
NF-κB signaling pathway (Zhang et al. 2017). Inflamma-
tory signaling could be amplified in neighbor cells in an
exosome-dependent manner. Thus, inflammasome-derived
exosomes might be used to augment the immune response,
and prevention of the transfer of these exosomes might
ameliorate immune-related diseases. In addition, inflamma-
some-derived exosomes are preferentially taken up by mac-
rophages, leading to the upregulation of NLRP3, process-
ing of caspase-1/IL-1β, and triggering of pyroptosis (Abal
2017; Wu et al. 1866). Growing evidence also indicates
that exosome-delivered miRs undergo functional transfer
among immune cells and constitute a mechanism of regula-
tion of the inflammatory response (Alexander et al. 2015).
A recent report demonstrated that M2 macrophage-derived
exosomes could carry miR-148a to alleviate myocardial
ischemia/reperfusion injury through inhibition of the TLR4/
NF-κB/NLRP3 (Dai et al. 2020). It has also been shown
that miR-9 inhibits NLRP3 inflammasome activation via the
JAK1/STAT1 pathway, and inhibition of miR-9 upregulates
NLRP3 inflammasome and caspase-1 expression (Jeyabal
et al. 2016; Wang et al. 2017).
Recent studies have revealed that exosome biogenesis
and autophagy share similar molecular machinery, and
these processes can be regulated by each other and play
important roles in health and disease. However, the cross-
regulation between these pathways is highly complicated
Archives of Toxicology (2021) 95:1141–1159 1153
(Xu et al. 2018). For instance, IL-1β secretion is inhibited
under basal autophagy and can be activated when autophagy
is induced in macrophages (Nakahira et al. 2011). Under
starvation conditions, IL-1β secretion, which lacks the signal
peptide sequence to follow the conventional ER-regulated
secretion pathway, is dramatically increased by the coor-
dinated action of ATG5, the inflammasome, GRASP, and
Rab8a via a mechanism known as autophagy-based uncon-
ventional secretion (Villarroya-Beltri et al. 2016). A recent
review article concluded that exosomal trafficking can play
a beneficial or harmful role in disease through the regulation
of autophagy (Lin et al. 2019). In addition, it showed that
autophagy plays a vital role in disease by regulating the gen-
eration of exosomes and that the cross-regulation between
exosomal and autophagic pathways may represent a promis-
ing target for disease prevention and treatment. Accordingly,
the exosome might serve as a bridge between the inflamma-
some and autophagy activation under the stress conditions,
including CO exposure. However, the detailed mechanisms
remain unclear and require further investigation.
Conclusions and perspectives
CO intoxication is the most common human poisoning
caused by gases and has a high mortality rate. In addition,
many survivors suffer from long-term morbidity involv-
ing multiple organ systems. The pathophysiology of COP
involves both the reduction of oxygen delivery and the
inhibition of mitochondrial respiration (Borzelleca 2000;
Rose et al. 2017). Excessive CO exposure disrupts the elec-
tron transport chain in mitochondria and produces ROS to
cause damages to cells or tissues (Fig. 3). COP-induced tis-
sue hypoxia is recognized as the major etiology of related
sequelae such as neurological symptoms, pulmonary edema
with respiratory failure, decreased myocardial contractil-
ity, arrhythmias, heart failure, and renal failure (Kinoshita
et al. 2020). In addition, CO may directly lead to cellular
changes involving immunological, inflammatory, and oxida-
tive stress-triggered damage via several defined mechanisms
(Hampson et al. 2012). Although cardiac and brain dysfunc-
tions are recognized as the major health effects occurring
after COP, subsequent complications are also noted in other
organ systems, including endocrine, gastrointestinal, and
respiratory systems. However, current COP biomarkers only
reflect acute CO exposure, and some of them are lack of
specificity. Thus, the identification of proper biomarkers to
predict complications and their severity following COP is a
main research goal in this field in the near future.
The cellular signaling networks modulated by CO
include several signal transduction pathways associ-
ated with the regulation of inflammation, cell death, and
cellular proliferation programs. An emerging concept is
that mitochondria may represent a common target of CO
and lead to subsequent mitochondria-derived mediators
and mtROS generation, which may be associated with
the regulation of downstream signaling effects of CO (Lo
Iacono et al. 2011; Ryter et al. 2018) (Fig. 4). Mitochon-
dria play a central role in many cellular functions, ranging
from energy status to cell fate. Thus, once mitochondria
dysfunction occurs, ROS are induced, and various path-
ways are activated, including the NLRP3 inflammasome,
pyroptosis, apoptosis, autophagy, and exosome release
pathways. Thus, modulation of cell mitochondria by CO
is a relevant subject for studying CO toxicity through the
downstream effects of mitochondria. This notion high-
lights the need for further research into the signaling
pathways which activate the NLRP3 inflammasome that
can, therefore, be targeted by appropriate inhibitors. More
studies are urgently needed.
The successful demonstration of inhaled CO in preclini-
cal animal models has led to continued efforts toward the
clinical application of CO, either through inhaled CO or
pharmacological delivery by CORMs. A recent clinical
trial demonstrated the feasibility of administering inhaled
CO to patients with COPD without any adverse effects. In
addition, the HO-1/CO system is implicated in numerous
cellular protective pathways. Therefore, there is a need
to reveal the link between the HO-1 and candidate genes
involved in various diseases to identify the actual role of
HO-1. This information will eventually help in making
HO-1 a potential therapeutic target for the amelioration
of various stress-related diseases.
In the context of the three-party interplay described
above, the exosome might have a pivotal impact on disease
by mediating autophagy and the inflammasome. However,
in contrast to the mechanisms involved in autophagy and
inflammasomes, much less is known about how exosome
regulates these processes under inflammatory conditions
related to CO exposure. Therefore, novel findings involving
mechanistic understanding of the modes of action for CO-
regulated pathways, including the abovementioned mecha-
nisms of NLRP3 inflammasome activation, autophagy, and
exosome release, are essential for the development of new
therapeutic strategies and biomarkers for COP.
We have thoroughly reviewed the beneficial and toxic
effects of CO, as well as the molecular pathways regulated
by CO in both scenarios. Given that the mitochondrion is
the major cellular target of CO exposure, it is worth men-
tioning again that further evaluating its downstream sign-
aling pathways could provide a solid basis for CO-based
therapy against diseases, a solution for COP treatment, and
a biomarker for COP monitoring (Fig. 4).
13

1154
Fig. 4  Possible mechanisms of regulation of inflammation in CO
toxicity. CO exerts direct effects by inhibiting mitochondria and
heme-like proteins, such as cytochrome c oxidase, promoting mito-
chondria ROS production and modulating mitochondria metabolism.
Acknowledgements This work was supported by the Minis-
try of Science and Technology, Taiwan through Grants MOST
108-2638-B-006-001-MY2, MOST 107-2311-B-006-004-MY3, MOST
108-2314-B-384-010, MOST 109-2314-B-384-005-MY3, MOST 108-
2314-B-039-061–MY3, MOST 109-2314-B-006-051-MY3, and MOST
108-2314-B-006-057. Figure 1 were created using BioRender.com.
Author contributions  R-JC writing—original draft, writing—review
and editing. Y-HL writing—original draft, writing—review and edit-
ing. T-HC writing—original draft. Y-YC writing—original draft. Y-LY
writing—original draft. C-PC conceptualization. C-CH conceptual-
ization. H-RG conceptualization, writing—review and editing. Y-JW
conceptualization, writing—original draft, writing—review and edit-
ing, supervision.
Compliance with ethical standards  303. https​://doi.org/10.1136/pgmj.69.810.302
Conflict of interest  The authors declare that they have no known com-
peting financial interests or personal relationships that could have ap-
peared to influence the work reported in this paper.
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