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MULTIPLE SCLEROSIS

Microglia clean up toxic lipids in multiple

sclerosis
Dong and colleagues investigated mechanisms mediating neurodegeneration in multiple sclerosis and identified a
direct role for oxidized phosphatidylcholines (OxPCs) in driving CNS cell death. Microglia activity, mediated by the
lipid sensor TREM2 and a neutralizing OxPC antibody, were capable of rescuing OxPC-induced neurotoxicity.

Kathryn M. Monroe and Gilbert Di Paolo

M
ultiple sclerosis (MS) is
an autoimmune disease
characterized by demyelination
and neurodegenerative processes, including
axonal damage and, in the most aggressive
cases, neuronal loss in the CNS. This
debilitating disease is a leading cause of
neurological disability in young adults,
with a majority of cases diagnosed between
the ages of 20–50. No causal genes have
been identified for MS; however, genome
wide association studies have identified
over 200 variants and implicated cells of
both the adaptive and innate immune
system1. The pathological hallmarks of
MS are demyelinating lesions in the brain
or spinal cord that are infiltrated with
self-reactive adaptive immune cells2. The
widely held view of MS disease progression
is that autoimmune lymphocytes attack
and destroy the myelin sheath, rendering
oligodendrocytes and axons susceptible
to death, which drives subsequent
neurodegeneration, but it remains unclear
whether myelin debris contribute to
neurotoxicity and if so, what mechanisms
are involved.
In this issue of Nature Neuroscience,
Dong et al. show that oxidized
phosphatidylcholines (OxPCs) are present
exclusively in MS lesions, but not in adjacent
normal white matter3. Prior to this work,
OxPCs were reported in MS lesions4, but
Dong et al. provide evidence that these
lipid species are pathogenic. Indeed,
they found a cell-type-specific response
to OxPCs characterized by neuron and
oligodendrocyte death and recruitment of
microglia/macrophages to the site of lipid
deposition (Fig. 1). In cell culture, OxPCs,
but not other non-oxidized phospholipids
or oxidized cholesteryl esters, induced
neuron and oligodendrocyte death, whereas
astrocytes were unaffected. These findings
translated in vivo, as oligodendrocytes were
rapidly depleted following OxPC injection,
and axonal degeneration was also observed.
The mechanisms mediating susceptibility
of neurons and oligodendrocytes and
protection of astrocytes to OxPC-induced
cell death were not investigated, but could be
of interest for future studies.
In addition to finding OxPC species
in MS patient lesions, Dong et al. also

a b

Fig. 1 | Proposed model of the role of TREM2+ microglia in clearing and detoxifying oxidized phospholipids in demyelinating MS lesions. a, OxPC species
accumulate in demyelinating lesions in the CNS of patients with MS and in mouse models and are neurotoxic in the CNS. OxPCs likely generated from
oxidative stress of myelin debris were detected in microglia, which express high levels of the innate immune receptor TREM2 and acquire diverse responsive
states in vivo. The IgV domain of TREM2 binds to myelin lipids and to OxPC, which enables TREM2+ microglia to clear these oxidized lipids, thereby
minimizing oxidative stress in the CNS. WT, wild type. b, In contrast, TREM2-deficient microglia, which have been shown to be arrested in a homeostatic state
and exhibit survival defects, have a reduced ability to take up OxPC, causing increased oxidative stress in the CNS and toxicity to neurons by inducing axon
dystrophy and death of neurons and oligodendrocytes.

Nature Neuroscience | VOL 24 | April 2021 | 451–456 | www.nature.com/natureneuroscience 451

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detected these toxic lipids in lesions of the
spinal cord and cerebellum in experimental
autoimmune encephalomyelitis (EAE), a
mouse model of MS (Fig. 1). OxPC species
were also deposited in spinal cord lesions
induced by injection of demyelinating
pro-inflammatory factors, such as ATP and
interleukin-1β (IL-1β), which function as
a trigger and product of inflammasomes,
respectively5. Direct injection of OxPC
was sufficient to induce demyelination and
neurodegeneration. Further supporting the
neurotoxic activity of OxPCs, co-injection
of the E06 anti-OxPC antibody neutralized
the toxic effects of exposure to synthetic
OxPCs or those produced endogenously
by ATP injection. Although the precise
origin of OxPCs in the CNS is unclear,
they likely are generated as a result of
oxidative stress within myelin debris, and
they may also be carried by apolipoproteins,
such as ApoE (Fig. 1).
Although human genetic studies
implicate a role for microglia, the
predominant brain-resident innate immune
cells, in MS, questions remain about
whether they promote or inhibit disease
progression. Excitingly, Dong et al. provide
evidence for a neuroprotective function for
microglia in response to OxPCs. Robust
recruitment of microglia expressing the lipid
sensor TREM2 was found in OxPC+ lesions
in human MS and EAE mouse models
(Fig. 1). Using an in vitro co-culture system,
the authors demonstrated a neuroprotective
role for microglia in preventing neuronal
death upon treatment with OxPCs or
another known neurotoxic lipid species,
lysolecithin. These results suggest that the
protective function of microglia in this
experimental system was not specific to
OxPC species, reflecting a more general
ability of microglia to scavenge toxic lipids.
Using a mouse model in which microglia
were selectively depleted, the authors
showed microglia are necessary to restrain
OxPC-mediated neurodegeneration in vivo.
Single-cell RNA-sequencing identified
nine diverse microglia/macrophage
sub-populations present in OxPC-induced
spinal cord lesions. Notably, all clusters
expressed high levels of TREM2, a
known lipid sensor and regulator of lipid
metabolism6,7. Surprisingly, established
myeloid OxPC receptors, such as CD36,
were not expressed at high levels in these
populations of microglia, suggesting that
other oxidized phospholipid receptors, such
as TREM2, may be involved. Accordingly,
TREM2 directly bound OxPCs and was
required for the neuroprotective activity of
microglia, as Trem2–/– microglia failed to
452
rescue OxPC-induced neuronal death both
in vitro and in vivo (Fig. 1).
Growing evidence, supported by
the findings of Dong et al., indicates
that microglia play a critical role in
metabolizing myelin debris in demyelination
paradigms. Myelin contains a considerable
amount of cholesterol, which needs to be
recycled and effluxed by microglia in a
process requiring APOE and TREM27–9.
Indeed, TREM2 is known to play a
pleiotropic role in myelin processing
by binding myelin-enriched lipids (for
example, sulfatides, phosphatidylserine)
and signaling through its co-receptor
DAP12 to activate a transcriptional profile
referred to as the disease-associated
microglia response6–8,10,11. The disease-
associated microglia response is required
for optimal lysosomal degradation and lipid
processing, among other activities7. Dong
et al. identified a specific mechanism by
which microglia exert a neuroprotective
effect, suggesting that TREM2 can bind
and clear toxic OxPCs, therefore acting as
a waste scavenger (Fig. 1). This extends
our functional understanding of TREM2
lipid–ligand interactions beyond solely
binding and activating receptor signaling.
While oxidized lipids have been previously
identified as ligands for TREM27,12,
this study indicates that one of the key
physiological functions of TREM2 may be
clearance of OxPC species that accumulate
in MS lesions, to minimize their toxicity
within the CNS (Fig. 1). The current study
does not address detoxifying pathways
downstream of TREM2 or the fate of OxPCs
in microglia, although these are interesting
directions for future research.
Notably, TREM2 is highly expressed in
microglia and has been identified through
human genetics studies as a key risk factor
for late onset Alzheimer’s disease (AD)11.
Ablation of TREM2 causes accumulation of
cholesteryl esters in cytosolic lipid droplets7.
This potentially implicates microglial lipid
metabolism as a key contributor to AD risk
and an important function of microglia
in the CNS. The mechanisms described
by Dong et al. certainly raise questions as
to whether OxPC species may contribute
to neurodegeneration in AD and whether
cleaning up neurotoxic lipid species is a
broadly applicable neuroprotective function
of microglia in the CNS.
With novel microglia targeting
therapies in clinical development for
AD11, it is tempting to speculate that
these could provide new opportunities
to improve the treatment of MS. Current
frontline MS therapies are directed toward
Nature Neuroscience | VOL 24 | April 2021 | 451–456 | www.nature.com/natureneuroscience
autoimmune T cells and B cells, with
positive outcomes for patients. While these
therapies certainly manage symptoms and
slow disease progression, it is well worth
considering harnessing the neuroprotective
functions of microglia to further improve
disease outcomes and slow or halt
neurodegeneration in MS. Enhancing
TREM2 function via an agonist antibody
is one such possibility. Recent studies
demonstrated TREM2 agonist antibodies
improve myelin debris clearance in
microglia in vitro and upon demyelinating
injury in vivo13–15. The impacts of enhancing
TREM2 innate immune signaling on the
adaptive immune system are not well
understood and require investigation if
this is to be a viable therapeutic strategy.
Additionally, inhibiting the inflammatory
responses that may generate OxPCs could be
effective in reducing the molecular drivers
of neurodegeneration. Elucidating and
selectively enhancing microglial pathways
mediating the catabolism of oxidized lipids
could also be a novel approach to promote
lipid detoxification in the CNS. Finally, as
demonstrated by Dong et al., the use of
antibodies neutralizing OxPCs may also
be considered for MS, given the emerging
preclinical evidence showing that this
approach confers benefits in a growing list of
diseases, including atherosclerosis16. ❐
Kathryn M. Monroe and
Gilbert Di Paolo    ✉
Denali Therapeutics Inc., South San Francisco,
CA, USA.
✉e-mail: dipaolo@dnli.com
Published online: 23 March 2021
https://doi.org/10.1038/s41593-021-00829-1
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Competing interests
The author declares no competing interests.