Best Practice & Research Clinical Anaesthesiology

Vol. 18, No. 3, pp. 407–424, 2004

doi:10.1016/j.bpa.2003.12.003
available online at http://www.sciencedirect.com

Inflammatory response after neurosurgery

Leman K. Mutlu MD
Research Associate
Department of Cell and Neurobiology, Institute of Anatomy, Humboldt University Medical School-Charité,
Berlin, Germany

Christian Woiciechowsky1
Attending Neurosurgeon
Department of Neurosurgery, Charité-Campus Virchow-Klinikum, Humboldt University Medical School-Charité,
Berlin, Germany

Ingo Bechmann*,1
Junior Professor of Anatomy
Department of Cell and Neurobiology, Institute of Anatomy, Humboldt University Medical School-Charité,
10098 Berlin, Germany

Investigation into the inflammatory response in the central nervous system (CNS) is a rapidly
growing field, and a vast amount of information on this topic has accumulated over the past two
decades. Inflammation is a particularly interesting issue in the (traditionally non-regenerating)
CNS, owing to its dual role in worsening or improving regeneration and functional outcome in
certain circumstances. This paper reviews the current literature on the interactions between the
immune system and the CNS in physiological and pathological states. The first part will provide an
overview of the cellular and molecular components of CNS inflammation, this being followed by a
discussion of the concept of systemic immunodepression after neurotrauma and neurosurgery.
Finally, the delicate balance of immune responses in the CNS, with an emphasis on the beneficial
effects of inflammation and possible therapeutic options, will be discussed.

Key words: central nervous system inflammation; cerebrospinal fluid cytokines; systemic
immunodepression; beneficial autoimmunity; myelin-inhibiting antibodies.

LOCAL INFLAMMATORY RESPONSE TO CNS INJURY

The initial injury to the central nervous system (CNS) caused by traumatic injury or
neurosurgical procedures is often aggravated by secondary insults that may occur with

* Corresponding author. Tel.: þ49-30-450-528267; Fax: þ49-30-450-528902.

E-mail address: ingo.bechmann@charite.de (I. Bechmann).
1
These authors contributed equally.

1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
408 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

Figure 1. Axial computed tomography (CT) of a patient with severe brain injury. (A –C) CT scans 2 hours
after the traumatic brain injury with some contusions in the frontal and temporal regions. (D–F) CT scans 4
days after the trauma. Over this time, new contusions have developed in the cerebellum and frontotemporal
area. The local inflammatory response in the brain contributes to this dynamic process and is associated with
the secondary injury syndrome.

a considerable delay after the initial impact, allowing for therapeutic intervention.1,2
The pathophysiology of secondary injury to the CNS is characterized by the activation
of distinct cascades leading to the release of various mediators and the activation of
neuronal death cascades, oedema and inflammation3 (Figures 1 and 2). Post-traumatic
inflammation in the CNS has the dual effect of aggravating damage and promoting
regeneration.4 – 6
Historically, CNS has been defined as an ‘immunologically privileged’ site. The
following findings suggest, however, that the parenchyma of the CNS can be
stimulated to create a microenvironment allowing the induction of productive
immune responses: connections between cerebrospinal fluid (CSF) compartments
and the cervical lymphatics;7 surveillance of the healthy CNS by T-cells;8 and major
histocompatibility complex (MHC) class II expression, primarily on the CNS
microglia, following CNS trauma.9,10 Evidence accumulating over the past two
decades has thus redefined the CNS from an ‘immunologically privileged’ to an
‘immunologically quiescent’ site.11
CNS lesions induce the activation of resident CNS cells and the infiltration of
leukocytes, triggered by a local up-regulation of cell adhesion molecules, chemokines
and cytokines.12
 Inflammatory response after neurosurgery 409

Figure 2. Axial computed tomography (CT) of a patient with cerebral ischaemia. (A) CT scan 2 hours after
the acute event without visible pathological changes. (B) CT scan 16 hours after the acute event with a
remarkable mass effect in the right frontotemporoparietal region with a hypodense area demonstrating an
infarct zone. (C) CT scan 48 hours after the acute event and 6 hours after decompressive craniotomy,
demonstrating a further enlargement of the infarct zone (left medial cerebral artery and left and right anterior
cerebral artery). Pro-inflammatory cytokines released into the brain are involved in this process of secondary
injury after focal cerebral ischaemia.

Cellular components of neuroinflammation

Stab wounds and axonal injury
A stab wound to the brain induces, within hours, activation of the microglia and
infiltration of the lesion site by haematogenous macrophages. Microglia proliferate and
demonstrate maximum activation over days 3 – 5.12,13 At this point, the distinction
between activated CNS microglia and haematogenous monocytes/macrophages is
difficult as microglia retract their thin processes (rounding of the cell body) and increase
their level of constitutively expressed complement receptor-3 (also known as CD11b
or ED-1 antigen) and MHC classes I and II. Reactive astrocytosis can also be detected,
as measured by an enhancement of immunoreactivity to glial fibrillary acidic protein
(GFAP) and increased cell size and number.9 It is hypothesized that activated astroglia
participate in reparative processes, for example, via the secretion of nerve growth
factor, promoting neuronal survival and the down-regulation of microglial activity by the
secretion of transforming growth factor-beta (TGF-b).14 Axonal injury does not induce
granulocytic infiltration.9

Focal cerebral ischemic lesions and contusional traumatic brain injury

Following ischaemia, intercellular adhesion molecule 1 (ICAM-1), P-selectin and E-
selectin are expressed on endothelial cells. These molecules interact with
complementary surface receptors on the neutrophils, which in turn adhere to the
endothelium, migrate through the vascular wall and enter the brain parenchyma.15
Neutrophil infiltration peaks 24 hours following infarction, after which the number
of granulocytes rapidly decreases. Neutrophils are followed by monocytes and
macrophages, which become the predominant cells in the area of the lesion 5– 7 days
after the ischaemic lesion. Leukocytic infiltration is associated with activation of the
resident CNS cells. Astrocytes become hypertrophic 4 –6 hours after ischaemia, when
microglia are also activated. Twenty-four hours after the ischaemic lesion, the microglial
reaction is well developed.15
410 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

Experimental studies on contusions have shown polymorphonuclear (PMN)

inflammatory cellular infiltration in the early stages and monocyte/lymphocyte
infiltration during the delayed phase of trauma. A study analysing biopsies of human
brain tissue that had undergone contusion showed a limited vascular margination of
PMN cells in the first 24 hours and a later massive inflammatory infiltration consisting
of monocytes, reactive microglia, PMN cells and T-lymphocytes.16

Spinal cord injury

Injury to the spinal cord leads to a more prominent inflammatory reaction than does
injury to the brain, as measured by the degree of neutrophil recruitment, the
expression of cellular adhesion molecule, the number of infiltrating macrophages and
the degree of breakdown of the blood –brain barrier (BBB).17

Molecular components of the local CNS inflammatory response

Owing to the fact that it is possible to measure the level of soluble molecules (including
adhesion molecules, cytokines and components of the complement system) in the CSF
of patients with head injury, there is growing amount of clinical data on their role
following CNS injury.

Complement system
The complement system is a key component of innate immunity, comprising nine
complement proteins that interact with different receptors and regulators. The
anaphylatoxin C5a represents one of the pivotal mediators of cerebral oedema,
breakdown of BBB function and intracranial recruitment of granulocytes.18 Its role in
traumatic brain injury (TBI) was investigated by an experimental study in which pre-
treatment with a recombinant soluble inhibitor of complement convertases led to a
reduction in intracranial neutrophil infiltration in the early stages.19 A study performed
on patients with severe closed head injury showed elevated levels of soluble membrane
attack complex (C5b-9) in the CSF. This correlated significantly with the extent of post-
traumatic BBB damage, suggesting a deleterious effect of complement activation in
TBI.20

Cytokines
Cytokines are small peptides released by almost all cell types. They are rapidly secreted
after CNS lesions and are essential for the initiation, propagation and termination of the
inflammatory response. They act through their high-affinity receptors, which are mainly
located on glial cells.21 Pro-inflammatory effects, neurotoxicity and brain oedema after
CNS injury are predominantly mediated by interleukin-1 (IL-1), IL-6, IL-8 and tumour
necrosis factor-alpha (TNF-a). Conversely, increases in IL-6, IL-8, IL-10 and TGF-b are
linked to anti-inflammatory processes or neurotrophin production and are thus
considered to have beneficial effects (some cytokines being classified as both pro- and
anti-inflammatory). Morganti-Kossmann et al have presented TNF, IL-6, IL-8, TGF-b
and IL-10 as the most thoroughly investigated cytokines in TBI.20 Studies in humans
usually measure the levels of both pro- and anti-inflammatory intrathecal cytokines
(indicative of the local inflammatory milieu) and compare them with serum cytokine
levels.
 Inflammatory response after neurosurgery 411

IL-6
Intrathecal levels of IL-6 are elevated following TBI or elective neurosurgery22 – 25 and
pass into the serum, as discussed below. IL-6 seems to be involved in stimulating the
astrocytic production of neurotrophins and might therefore also be involved in
regenerative processes.20

TNF-a
TNF-a is a 17 kDa peptide that plays a significant role in CNS inflammation. It is
produced by activated macrophages, T-cells, astrocytes, microglia and neurons, and
increases in the CSF shortly after TBI.25 High intrathecal levels of TNF-a were found in
the early stages after surgery in patients with intra-axial (but not extra-axial) tumours23,
supporting the idea of its synthesis by resident CNS cells. Studies in which the specific
inhibition of TNF resulted in attenuated BBB impairment and cerebral oedema have
demonstrated that TNF-a has detrimental effects in TBI.26 Conversely, studies have
demonstrated surprisingly worse outcomes after CNS trauma and experimental
autoimmune encephalomyelitis (EAE, the animal model of multiple sclerosis) in TNF-a
knockout animals than in wild-type controls, suggesting a beneficial role of TNF-a in
neuroinflammation.27,28 This discrepancy suggests that TNF-a may have deleterious
effects in early stages of CNS injury and possibly beneficial effects in its late stages.

IL-10
Experimental studies show that IL-10 is synthesized by numerous cells, including Th
cells, monocytes/macrophages, astrocytes and microglia. It is induced by and inhibits
the production of pro-inflammatory cytokines such as TNF-a and IL-6. It also inhibits
MHC class II expression and T-cell proliferation.29
The first study demonstrating an increase in IL-10 in the CSF following TBI was
performed on paediatric patients. The increase occurred in the first 3 days after injury,
along with a dramatic elevation in IL-6.30 Intrathecal IL-10 levels in adult TBI patients
increased at the same time after trauma. Furthermore, an intrathecal IL-10 production
was suggested based on the evidence that CSF levels were higher than serum levels.25
The kinetics of IL-10 and IL-6 show similar patterns in CSF and serum, whereas TNF-a
and IL-10 demonstrate an inverse relationship, suggesting that the former may induce
the latter.25
In vivo studies have demonstrated that the local administration of IL-10 attenuates
reactive astrocytosis and microglial activation, as well as diminishing the expression of
TNF-a mRNA.31 Following spinal cord injury (SCI), the systemic administration of IL-
10 (30 minutes after injury) reduced inflammation and was neuroprotective, as
measured by a reduction on lesion volume and improved motor function.32 However,
the association between higher levels of IL-10 in the CSF of brain-injured children and
increased mortality makes its neuroprotective role uncertain.30

TGF-b
TGF-b comprises a family of cytokines with anti-inflammatory properties similar to
those of IL-10. There are conflicting results regarding the elevation of TGF-b following
TBI.25,33 TGF-b is present in high levels in the serum of control individuals, and some
studies show an increase in the serum fraction compared with its CSF level, suggesting a
correlation with BBB dysfunction.33 Both TGF-b and IL-10 are known to induce
regulatory T-cells, which suppress T-cell immunity, for example, against myelin
components.34
412 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

SYSTEMIC EFFECTS OF THE INFLAMMATORY RESPONSE AFTER

CNS INJURY

Passage of brain-derived cytokines into the circulation

It is known that brain damage is associated with the appearance of different immune
mediators in the plasma.22,35 Various studies have described increased plasma levels of
different soluble mediators such protein S-100, ICAMs, selectins, IL-4, IL-6, IL-8 and IL-
10 after different types of brain injury.22,36 – 38 In a clinical study involving brain-injured
patients, we were able to demonstrate an impressive neuroendocrine and
inflammatory response shortly after the acute event. We demonstrated for the first
time, in both a retrospective and a prospective study, that concentrations of IL-6 on day
1 after the acute event with a cut-off point of 100 pg/ml have an excellent predictive
value with regard to short-term recovery, infectious complications and mortality.39
Kossmann and co-workers reported that patients with severe TBI showed a
profound acute-phase response. IL-6 levels were monitored in the CSF and serum of
patients with severe isolated TBI. The CSF/serum albumin ratio served as a parameter
of BBB dysfunction. A correlation between CSF and serum IL-6 was found initially after
the trauma and corresponded to severe dysfunction of the BBB. Maximum IL-6
concentrations in serum correlated with peak levels of acute-phase proteins (C-
reactive protein, alpha-1-antitrypsin and fibrinogen). The results show that the increase
in IL-6 level in the CSF and serum is followed by a profound acute-phase response in
patients with TBI. Because cytokine concentrations are significantly lower in serum
than CSF, it was hypothesized that IL-6 produced in the CNS might be initiating the
acute-phase response.22 Furthermore, there is some evidence that plasma levels of IL-6
correspond to infarct volume after cerebral ischaemia, suggesting a hypoxia-induced
local production in association with the extent of brain injury.35 In summary, IL-6 is
locally released in the injured brain tissue depending on the size of the brain tissue
damage and secondarily passes into the circulation.35,40
Stahel and co-workers showed that mean levels of IL-12 in the CSF were significantly
elevated in patients with severe head trauma. IL-12 is a key inducer of the differentiation
of uncommitted Th cells toward the Th1 phenotype, which regulates cellular immunity.
Assessment of the CSF/serum ratio of IL-12 and of BBB function, using the CSF/serum
albumin ratio, suggested that elevated CSF levels of IL-12 might be in part derived from
intracerebral cytokine synthesis.41 Arand et al performed a prospective pre-clinical and
clinical study in order to determine important pro- and anti-inflammatory mediators
with regard to the survival and outcome of patients with severe TBI. They showed that
maximum plasma levels of IL-6 were eight times higher in non-surviving patients.
Furthermore, these patients were the only ones to express an increase in IL-12,
whereas survivors and patients with other major trauma did not show any increase in
IL-12 within the first 24 hours.24 Maier et al showed that IL-6 and IL-8 were significantly
increased in CSF and plasma compared with baseline levels in the early stages after
trauma. In all patients, CSF levels of IL-6 and IL-8 were found to be higher than
corresponding plasma levels. IL-10 in plasma was significantly increased above control
plasma values, but it was unchanged in the CSF.42 The results suggest that IL-6 and IL-8
are produced in the brain and trespass into the circulation, whereas IL-10 is additionally
produced by blood cells. Our studies confirmed that the systemic increase in IL-10
following brain injury results from the release of pre-formed IL-10 as a result of the
sympathetic activation of peripheral monocytes/macrophages (together with brain IL-
10 production), whereas IL-6 seems to be released locally in the injured brain tissue,
 Inflammatory response after neurosurgery 413

from whence it passes into the circulation.39 In summary, brain injury and ischaemia are
associated with a systemic increase in pro- and anti-inflammatory cytokines owing to
the transpass of brain cytokines into the plasma after the BBB has been disrupted.22,35
In this scenario of a mixed antagonistic response syndrome, the anti-inflammatory
response dominates and leads to a brain-mediated immunodepression with an
increased risk of developing infectious complications (Figure 3).

Mechanisms of systemic immunodepression

Overwhelming inflammatory immune response can result in systemic inflammation (the

systemic immune response syndrome) and septic shock. In order to prevent an
excessive and deleterious action of pro-inflammatory cytokines, the immune system
can release several anti-inflammatory mediators, for example, IL-10, IL-1 receptor
antagonist, TGF-b and soluble TNF receptors, initiating a compensatory anti-
inflammatory response syndrome. Furthermore, in vivo, the delicate balance between
the pro- and anti-inflammatory responses is additionally controlled by the CNS. Clinical
studies suggest that the immune system can activate the hypothalamic-pituitary-adrenal
(HPA) axis as well as the autonomic nervous system and provide a shortcut by which
the immune recognition of an infectious challenge can rapidly induce the secretion of
neuroimmune modulators such as glucocorticoids, adrenocorticotropic hormone
(ACTH), alpha-melanocyte-stimulating hormone (MSH), catecholamines and acetyl-
choline. These mediators can again suppress immune cell function in order to control
systemic inflammation and establish homeostasis.43
However, what happens if the immuno-inhibitory CNS pathways are activated
without a significant systemic inflammation? This can result from the production of
cytokines in the brain following infection, injury, ischaemia and neurosurgical
procedures (as previously described), or directly from brainstem irritation.40

Activation of the HPA axis by brain cytokines with consequences for the systemic immune
response
Besedovsky and del Rey were the first to demonstrate the existence of an
immunoregulatory feedback circuit in which IL-1 acted as afferent and glucocorticoids
as efferent signal vectors.44 Interestingly, various sites of IL-1 injection, either
intraperitoneally44, intravenously45 or intracerebroventricularly46, provoked dose-
related increases in the plasma concentrations of ACTH and corticosterone in rats.
Other cytokines, for example, IL-6, IL-12, interferon-gamma (IFN-g) and TNF-a can
also act centrally to stimulate the HPA axis and induce a subsequent release of ACTH,
a-MSH and glucocorticoids (Figure 3).47
In this scenario, glucocorticoids are well known for their anti-inflammatory and
immunosuppressive properties. They restrain the production of pro-inflammatory
cytokines (IL-1, TNF-a) and enhance the release of TGF-b. Also, in vivo, they augment
the secretion of IL-10.48 Furthermore, glucocorticoids suppress the expression of
MHC class II molecules such as HLA-DR on antigen-presenting cells and inhibit various
lymphocyte functions.49 Elenkov et al demonstrated that dexamethasone inhibited
lipopolysaccharide-induced bioactive IL-12 production in human whole blood in a dose-
dependent fashion and at physiologically relevant concentrations; however, it has no
effect on IL-10 secretion. The glucocorticoid-induced reduction of IL-12 production
was antagonized by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was
414 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

Neurosurgery Brain injury

IL-1b­, IL-10­, IL-6­, IL-8­, IL-12­, TNF-a­

Disruption of the BBB HPA-axis Autonomic NS

Passage of brain Glucocorticoids Catecholamines

cytokines into blood ACTH Acetylcholine
α-MSH Nicotine

Immune cells

IL-1b­, IL-6­, IL- 8­ TNF-a¯, IL-6¯, IL-12¯,

IL-12­, TNF-a­, IL-10­ IFN-g¯, TGF-b­, IL-10­

Mixed antagonistic response syndrome (MARS)

Immunodepression

Pneumonia

INFLAMMATION

Figure 3. Mechanism of brain inflammation-induced systemic immunodepression. Pro- and anti-

inflammatory cytokines are produced in the brain after infection, injury and ischaemia. Microglia, astrocytes
and blood-derived immune cells are the main source of this cytokine production. Furthermore, the local
 Inflammatory response after neurosurgery 415

mediated by the glucocorticoid receptor.50 Interestingly, it was shown that there are
antagonistic interactions between nuclear factor-kappa B (NF-kB), a key pro-
inflammatory transcription factor, and ligand-activated glucocorticoids receptors.
This could explain how glucocorticoids inhibit the production of pro-inflammatory
cytokines that do not have glucocorticoid-responsive elements in their promoters.51
The importance of the HPA axis in controlling systemic inflammation has been
demonstrated in many in vivo animal studies. Rats with an intact HPA axis showed
marked resilience and adaptability in tolerating very high doses of endotoxin (4 –
40 mg/kg) and IL-1b (60 mg/kg) during monitoring over 12 hours.52 In contrast,
adrenalectomized or hypophysectomized animals exhibited a largely increased
sensitivity to the lethal effects of endotoxin, IL-1b and TNF-a.52 However, the intra-
brain application of IL-1b in rats stimulated the HPA axis without any systemic
inflammatory challenge.53 This might cause an immunodepression in an unstimulated
immune system. It was shown that an infusion of IL-1b into the rat brain produced a
rapid suppression of natural killer cell activity, a diminished response to phytohae-
magglutinin stimulation and a decreased production of IL-2.54
We have shown that cerebral inflammation resulting from the intracerebroven-
tricular or intra-hypothalamic infusion of rat recombinant IL-1b particularly diminished
the level of endotoxin-induced TNF-a but increased the IL-10 concentration in
stimulated whole-blood cultures. Blocking the HPA axis by hypophysectomy led to a
complete recovery of the diminished TNF-a concentration and temporarily inhibited
the increase in IL-10.55 Moreover, an intracerebroventricular and intra-hypothalamic
infusion of IL-1b dramatically increased neutrophil counts, whereas lymphocyte counts
dropped. Blocking the HPA axis by hypophysectomy abolished the neutrophilia while
the lymphopenia remained unchanged. All parameters normalized within 48 hours of
termination of the infusion.56 Furthermore, a variety of experimental studies have
described a corticosteroid-independent mechanism of hypothalamus-pituitary-
mediated immunodepression.
It has been suggested that a-MSH is involved in this process. The immuno-
modulating capacity of a-MSH may be primarily the result of its effects on melanocortin
receptor-expressing monocytes, macrophages and dendritic cells. a-MSH down-
regulates the production of pro-inflammatory cytokines such as IL-1, IL-6, TNF-a, IL-2,
IFN-g, IL-4 and IL-13 as well as the expression of co-stimulatory molecules (CD86,
CD40, ICAM-1) on antigen-presenting cells. In contrast, the production of the anti-
inflammatory cytokine IL-10 is up-regulated by a-MSH. At the molecular level, these
effects of a-MSH are mediated by inhibiting the activation of transcription factors such
as NF-kB.57
Finally, numerous clinical studies have demonstrated that peripheral blood
lymphocytes obtained from patients with malignant brain tumours responded poorly
to mitogens and antigens; the production of Th cell cytokines (IL-2, IFN-g,

pro-inflammatory response in the brain may activate neuroimmune pathways such as the hypothalamic
pituitary adrenal axis and the autonomic nervous system, and trigger a systemic anti-inflammatory response.
Brain cytokines can, however, also pass into the circulation when the blood–brain barrier is disrupted. This
may additionally generate a systemic inflammatory response syndrome. In combination with the anti-
inflammatory response, this may lead to a mixed antagonistic response syndrome. However, after various
kinds of brain injury, the balance between the brain-mediated pro- and anti-inflammatory response is
remarkably shifted to a predominance of anti-inflammatory cytokines, producing immunodepression with a
high risk of infection. A developed infection, for example, pneumonia, may itself produce a systemic
inflammation with high levels of pro-inflammatory cytokines. These cytokines may act on the injured brain and
increase brain oedema as well as worsening the outcome of the secondary injury syndrome.
416 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

granulocyte/monocyte colony-stimulating factor [GM-CSF]) and the expression of IL-2

receptors after mitogenic stimulation were significantly lower than those of T-cells
obtained from normal individuals.58. Furthermore, we were able to show for the first
time that, in glioblastoma patients, the function of not only lymphocytes, but also
monocytes was impaired. Our data demonstrated a decreased monocytic HLA-DR
expression and ex vivo secretion capacity for pro-inflammatory cytokines. Monocyte
deactivation in glioblastoma patients could be partially restored by tumour
extirpation.59 Interestingly, brain tumours produce an immense diversity of pro- and
anti-inflammatory cytokines.60
We have also demonstrated that neurosurgical procedures and TBI are associated
with a post-operative release of cytokines into the CSF. This corresponded closely to a
decreased monocytic HLA-DR expression as sign of systemic immunodepression. If the
percentage of monocytes expressing HLA-DR molecules was lower than 30% in our
assay during the first 3 days after neurosurgery, this was closely related to the
development of infectious complications (predictive value 0.9).23,40,61,62 The monocytic
deactivation was linked to a stimulation of the HPA axis, probably by pro-inflammatory
cytokines in the CSF.61

Activation of the autonomic nervous system by brain cytokines with consequences

for the systemic immune response
It has recently been shown that primary and secondary lymphoid organs are innervated
extensively by noradrenergic sympathetic nerve fibres63, and that monocytes/
macrophages and other immune cells bear functional adrenoreceptors. Moreover,
lymphocytes are known to possess both muscarinic and nicotinic acetylcholine
receptors.64 Recent evidence suggests that norepinephrine and epinephrine, via
stimulation of the beta-2-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the
production of type 1/pro-inflammatory cytokines by antigen-presenting cells and Th1
cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such
as IL-10 and TGF-b. Via this mechanism, endogenous catecholamines may cause a
selective suppression of Th1 responses and cellular immunity and a Th2 shift towards
the dominance of humoural immunity, similar to the action of glucocorticoids. On the
other hand, catecholamines may actually boost regional immune responses through the
induction of IL-1, TNF-a and primarily IL-8 production. Thus, the activation of the
autonomic nervous system during an immune response might be aimed at localizing the
inflammatory response through the induction of neutrophil accumulation and the
stimulation of more specific humoural immune responses, although systemically it may
suppress Th1 responses and thus protect the organism from the detrimental effects of
pro-inflammatory cytokines.63
It seems likely that corticotropin-releasing factor (CRF) plays a key role for the brain
IL-1b-triggered activation of the sympathetic nervous system (SNS).65 This hypothesis
is supported by the observation that the brain IL-1b-induced impairment of T-cell
proliferation and natural killer cell activity in adrenalectomized rats can be prevented by
the application of neutralizing anti-CRF antibodies.65
It has been demonstrated that catecholamines inhibit the monocytic production of
TNF-a after endotoxin stimulation.66 Furthermore, an increased TNF-a production by
peritoneal macrophages obtained from sympathectomized mice was observed.67 The
pre-exposure of mononuclear cells to epinephrine or norepinephrine not only inhibited
the endotoxin-induced production of TNF-a, but also increased IL-10 release.68 These
findings were proven in healthy volunteers.
 Inflammatory response after neurosurgery 417

In addition, we showed that, within minutes, catecholamines triggered the secretion

of IL-10 from monocytes through beta-adrenoreceptor stimulation.40 Moreover, in a
rat model, increased intracranial pressure leading to sympathetic activation rapidly
induced an impressive systemic IL-10 release. This effect could be blocked by the beta-
adrenoreceptor antagonist propranolol.40 Elenkov et al showed that norepinephrine
and epinephrine suppressed IL-12 production in a dose-dependent fashion and at
physiological concentrations; both catecholamines, however, dose-dependently
increased the production of IL-10. The effects of either catecholamine on IL-12 or
IL-10 secretion were blocked completely by propranolol.50 These findings also support
the hypothesis that the CNS may regulate IL-12 and IL-10 secretion and hence Th1/Th2
balance via the sympathetic nervous system. Thus, stimulation of the sympathetic
nervous system may cause a shift toward a Th2 cytokine pattern rather than
generalized Th suppression.
Furthermore, direct electrical stimulation of the peripheral vagus nerve in vivo
during lethal endotoxaemia in rats inhibited TNF synthesis in the liver, attenuated peak
serum levels of TNF and prevented the development of shock.69 This vagus-mediated
mechanism represents the cholinergic anti-inflammatory pathway complementary to
the adrenergic anti-inflammatory pathway of the autonomic nervous system described
previously (Figure 3).
In our clinical studies, we showed that brain-injured patients have high plasma levels
of IL-10 immediately after the trauma. This correlated with signs of increased
intracranial pressure and sympathetic activation as well as with an increased risk of
infectious complications.40 Similar findings could be seen in patients after neurosurgical
procedures, where we observed that manipulations of the brainstem with activation of
the sympathetic nervous system led to monocyte deactivation and increased IL-10
production. This situation produces an immunodepression and an increased risk of
developing infectious complications.40 In summary, if these pathways are activated
without systemic inflammation, as with brain trauma or neurosurgery, this may cause
brain-mediated immunodepression (Figure 3).

BENEFICIAL EFFECTS OF NEUROINFLAMMATION: A THERAPEUTIC

OPTION?

Innate and adaptive immunity within the immune-privileged CNS

Immune responses have to be balanced such that their helpful effects are not exceeded
by inflammation-induced secondary damage to intrinsic cells.
In the CNS, at the level of the innate immune system, microglia are suppressed in
their phagocytic and antigen-presenting capacity by intrinsic signals such as astrocytic
TGF-b.14 The adaptive immune system is restrained by the BBB and by organ-specific
factors that induce T-cell apoptosis, suppress T-cell proliferation or provide a poor
environment for the activation of microglia to mature antigen-presenting cells (for a
review, see Ref. [70]). At the level of antigen presentation, innate and adaptive immunity
are linked: antigen presentation by immature antigen-presenting cells leads to T-cell
anergy and apoptosis or the differentiation of regulatory/Th3-like T-cells. Since the
microglia in their local environment are indeed difficult to activate towards mature
antigen-presenting cells, providing full blast co-stimulation and pro-inflammatory
signalling to support strong Th1 or Th2 responses71, re-stimulation by immature
microglia within the lesioned CNS largely directs T-cells into regulatory/anergic
418 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

differentiation. Only a multistep activation process involving both stimulation via

cytokines (GM-CSF and IFN-g) and cognate signalling (B7-CD28 and CD40-CD40
ligand interactions), as it occurs during certain forms of infectious encephalitis and
autoimmune conditions such as multiple sclerosis, transforms the microglia into mature
antigen-presenting cells.72,73 To our knowledge, this occurs in vivo only when T-
lymphocytes activated in the lymphoid organs invade the CNS in large numbers, where
they trigger microglial maturation.74 For a limited period, microglia support (often
inadequately) strong T-cell immunity, leading to tissue damage and neurological deficits.
Interestingly, such T-cell responses within the CNS are mostly self-limiting, showing that
tight regulatory mechanisms readily maintain immune tolerance. From a therapeutic
point of view, there is the possibility of modulating immune responses such that they
provide more help and less damage to the lesioned tissues.

Immune suppression as a cause of limited regeneration

Immune suppression in the CNS may have its evolutionary meaning in protecting the
neurons, which cannot easily be replaced. What is, however, helpful under infectious
conditions appears to be partially responsible for the poor capacity of the CNS to
regenerate following mechanical lesions. There is now evidence that the same
mechanisms that meaningfully suppress immune responses to infection also inhibit
regeneration by annulling the helpful qualities of the immune response.
It has long been appreciated that axons within the CNS have a very limited capacity
to regrow after receiving a lesion. Although the axons of peripheral nerves are capable
of regenerating over long distances, axotomized fibres in the CNS are hardly able to
cross the site of the lesion. This is not a principle failure of CNS neurons because they
are able to grow into a permissive environment (e.g. peripheral nerve segments) and
exhibit impressive short-distance plasticity (axonal sprouting and reactive synaptogen-
esis).75
A strong inhibition of axonal regeneration after lesioning derives from the presence
at the lesion site of certain myelin epitopes, for example, NOGO, which form a myelin
debris, not permitting regrowth (for a review, see Ref. [76]). Interestingly, because of
the local inhibition of microglial phagocytic activity, the removal of growth-inhibiting
myelin debris is delayed in the CNS compared with the peripheral nerves.77 This may be
one way in which the local immune-suppressive environment within the CNS negatively
affects regeneration. In fact, boosting the innate and adaptive immune responses after
mechanical injury has been shown to enhance functional regeneration. Schwartz and
co-workers found that the injection of activated macrophages and myelin-specific T-
cells enhanced functional regeneration following an axonal lesion within the CNS.78,79
Moreover, immunization with myelin epitopes concomitant with SCI enhanced the
axonal growth and recovery of certain hind limb motor functions.80 Following aseptic
cerebral injury, myelin-specific T-cells accelerated post-traumatic revascularization and
healing.81 Actively induced EAE improved motoneuron survival after dorsal root
avulsion in adult rats.82 Therefore, boosting the immune response to CNS injury under
certain conditions may be more beneficial than harmful to functional regeneration. In
fact, the first clinical trials of macrophage transfer after SCI are already underway.83
The picture is, however, more complex than this. There is substantial evidence that
immune responses following CNS trauma cause additional harm and finally hamper
functional outcome. Popovich et al have shown that the depletion of macrophages prior
to a spinal cord lesion improves functional regeneration.84 Moreover, they reported
that mice with a transgenic T-cell receptor specific to myelin exhibited worse functional
 Inflammatory response after neurosurgery 419

recovery than mice of the same genetic background.85 There is evidence that the
capability of strains to develop strong autoimmune responses to myelin negatively
correlates with their immune system’s capability to enhance regeneration. EAE-
susceptible mice were less capable of mounting protective immune responses than
were resistant strains.86 It thus appears that macrophages and T-lymphocytes
simultaneously provide protective and destructive signals; therefore the actual lesion,
the genetic background and not least the parameters for evaluating regeneration
determine whether positive or negative effects predominate.
Consequently, a whole field of research is now trying to define the role of immune
cells, primarily T-cells and macrophages, in regeneration. In most models, it is currently
unclear whether T-cell responses improve functional outcome by reducing cell loss
(neuroprotection), by enhancing regenerative processes such as axonal outgrowth/-
sprouting or by a combination these. T-cells have recently been found to secrete
neurotrophins such as nerve growth factor, brain derived neurotrofic factor, (BDNF)
and neurotrophin 3 (NT-387), but the relevance of this secretion in vivo after lesioning
remains uncertain. With regard to functional outcome, another positive effect may
derive from a T-cell-mediated activation of microglial phagocytosis74,88, leading to an
enhanced removal of growth-inhibiting debris. In fact, specifically targeting growth-
inhibiting myelin epitopes with monoclonal or polyclonal antibodies also dramatically
enhances axonal growth in several models of CNS injury80,89,90, supporting the concept
that myelin-mediated growth inhibition can be overcome by novel therapeutic
approaches.

SUMMARY

Inflammation following neurosurgery and neurotrauma is a major secondary injury

mechanism with putative regeneration-promoting properties. Its cellular components
involve resident CNS cells and infiltrating leukocytes. Focal ischaemia and contusional
injury use the same mechanisms of cellular recruitment to the lesion site: the up-
regulation of adhesion molecules and cellular activation via the expression of
chemokine and cytokine molecules. The release of these molecular components of
neuroinflammation has not only local, but also systemic effects. Pro-inflammatory
cytokines ‘spill’ over from the CSF to the systemic circulation and induce brain-
mediated systemic immunodepression. HPA axis and autonomic nervous system
activation lead to additional immunosuppression, which leads to severe infectious
complication in neurosurgical/TBI patients.
Therapeutically promising progress has recently been made in the field of
neuroregeneration. Autoreactive T-cells and macrophages improved functional out-
come when transferred to CNS-injured animals, the same results being obtained by
vaccinating injured animals against CNS myelin. Schwab et al76 have discovered that
blocking myelin epitopes with specific antibodies promotes axonal regrowth after SCI.
Many questions, however, remain unanswered. Safe strategies require a detailed
knowledge of how immune tolerance is regulated after CNS injury and how
regeneration is supported by immune cells in order to avoid systemic autoimmunity
and secondary damage induced by therapeutic intervention. It is, however, now clear
that modulating immune responses to brain and SCI can significantly improve post-
lesional neurological outcome, and there is the potential to uncover and fruitfully
support the underlying pathways.
420 L. K. Mutlu, C. Woiciechowsky and I. Bechmann

Practice points
† neurosurgical procedures and TBI are associated with a post-operative
cytokine release into the CSF and systemic immunodepression (mediated by
the HPA axis and sympathetic nervous system), which leads to infectious
complications. It should always be borne in mind that TBI/neurosurgery
patients are immunosuppressed
† plasma concentrations of IL-6 on day 1 after TBI with a cut-off point of
100 pg/ml have been shown to be an excellent predictor of short-term
recovery, infectious complications and mortality
† clinical studies on promoting axonal regeneration using autologous T-cells and
macrophages and myelin-inhibiting antibodies are underway, but more research
is needed to determine the safety of these treatments

Research agenda
† the CNS is an extremely ‘hostile’ microenvironment to inflammation: it induces
T-cell apoptosis, suppresses T-cell proliferation and provides a poor
environment for the activation of microglia to mature antigen-presenting cells
† the local immune-suppressive environment within the CNS negatively affects
regeneration; more research is needed to determine ways of modulating
immune responses such that they provide more help and less damage for the
lesioned CNS
† the beta-adrenergic blocker propranolol seems to be a promising option in
ameliorating cathecolaminergic induction of the immunosuppresive IL-10
† boosting innate and adaptive immune responses after mechanical injury has
been shown to enhance functional regeneration in the CNS

ACKNOWLEDGEMENTS

The authors wish to thank Mr Nicholas Hubble for critically reading the manuscript.

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