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Distinct Gene Profiles of Bone Marrow-Derived Macrophages and Microglia During Neurotropic Coronavirus-Induced Demyelination

ABSTRACT: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are associated with infiltrating T lymphocytes, bone marrow-derived macrophages (BMDM), and activated resident microglia. Tissue damage is thought to be mediated by T cell produced cytokines and chemokines, which activate microglia and/or BMDM to both strip myelin and produce toxic factors, ultimately damaging axons and promoting disability. However, the relative contributions of BMDM and microglia to demyelinating pathology are unclear, as their identification in MS tissue is difficult due to similar morphology and indistinguishable surface markers when activated. The CD4 T cell-induced autoimmune murine model of MS, experimental autoimmune encephalitis (EAE), in which BMDM are essential for demyelination, has revealed pathogenic and repair-promoting phenotypes associated with BMDM and microglia, respectively. Using a murine model of demyelination induced by a gliatropic coronavirus, in which BMDM are redundant for demyelination, we herein characterize gene expression profiles of BMDM versus microglia associated with demyelination. While gene expression in CNS infiltrating BMDM was upregulated early following infection and subsequently sustained, microglia expressed a more dynamic gene profile with extensive mRNA upregulation coinciding with peak demyelination after viral control. This delayed microglia response comprised a highly pro-inflammatory and phagocytic profile. Furthermore, while BMDM exhibited a mixed phenotype of M1 and M2 markers, microglia repressed the vast majority of M2-markers. Overall, these data support a pro-inflammatory and pathogenic role of microglia temporally remote from viral control, whereas BMDM retained their gene expression profile independent of the changing environment. As demyelination is caused by multifactorial insults, our results highlight the plasticity of microglia in responding to distinct inflammatory settings, which may be relevant for MS pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE214472 | GEO | 2022/10/02

REPOSITORIES: GEO

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Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) plays a protective role in neurodegenerative diseases, including Alzheimer’s and demyelinating diseases. However, Trem2 functions can exacerbate tissue damage during viral respiratory or liver infections. We therefore investigated the role of TREM2 in a viral encephalomyelitis model associated with prominent Th1 responses and demyelination. To address our hypothesis, Wild type (WT) and Trem2-/- mice were infected with a sublethal glia tropic murine coronavirus (MHV-JHM) was intracranially. Disease progression and survival were monitored daily. Immune response and demyelination in the spinal cord (SC) were determined by flow cytometry and immunofluorescences analysis. Expression of Inflammatory cytokines was measured with RT-PCR. Differential gene expression in sorted SC-derived microglia and infiltrated bone marrow-derived macrophages (BMDM) were determined by Nanostring, nCounter system, which directly captures and counts individual mRNA transcripts thereby omitting cDNA-based amplification. Upon infection, BMDM highly upregulated Trem2 mRNA compared to microglia, which showed a delayed increase coincident with demyelination. Although TREM2 deficiency did not alter disease onset and severity, it impaired clinical recovery during establishment of viral persistence associated with demyelination. Disease progression in Trem2-/- mice was not associated with altered virus control, leukocyte recruitment or overall inflammatory responses in the SC. However, there was a significant increase in degenerated myelin not associated with the myeloid markers IBA1 and/or CD68 in the lesions. Gene expression profiles of SC-derived microglia and BMDM using the Nanostring platform revealed that TREM2 deficiency resulted in the failure to upregulate genes associated with phagocytosis, including LPL and CD36. Overall our data using a virus infection model show that TREM2 deficiency does not affect viral control or T cell immunity but leads to impaired expression of select phagocytic pathway factors, ultimately resulting in failure to remove damaged myelin in demyelinated lesions. The results support that TREM2 dependent removal of damaged myelin is independent of the initial insult or the inflammatory milieu, but rather regulated by sensing a dysregulated lipid environment.

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Distinct Gene Profiles of Bone Marrow-Derived Macrophages and Microglia During Neurotropic Coronavirus-Induced Demyelination

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