Abstract
Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics.
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•TREM2 ablation in microglia leads to transient protection at the acute stage of SCI and EAE•Different levels of TREM2 characterize distinct macrophage phenotypes in SCI versus EAE•TREM2 ablation reduces macrophage phagocytic phenotype leading to neuroprotection in SCI•TREM2 ablation induces monocyte lysosome-activated phenotype worsening demyelination in EAE
Gao et al. identify the existence of two distinct phenotypes of microglia and infiltrating myeloid cells dependent on TREM2 expression levels at the acute stage of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE), and the authors elucidate how they mediate the opposing effects of TREM2 in the two disorder models.
