Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination

Abstract

Background Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. Methods Wild-type (WT) and Trem2 deficient (Trem2−/−) mice were infected with a sublethal glia tropic murine coronavirus (MHV–JHM) intracranially. Disease progression and survival were monitored daily. Leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone-marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform. Results BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2−/− mice could not be attributed to altered virus control or an elevated proinflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genes Lpl and Cd36 in microglia, but a more complex pattern in BMDM. Conclusions Trem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments.

Cystatin F attenuates neuroinflammation and demyelination following murine coronavirus infection of the central nervous system

“…Impaired phagocytosis of myelin debris by myeloid cells has been associated with impaired remyelination in JHMV-infected mice [ 28 , 36 , 50 ]. Therefore, one potential pathway associated with inefficient remyelination in JHMV-infected mice includes reduced phagocytosis of myelin debris by microglia.…”

“…Impaired remyelination in JHMV-infected Cst7-/- mice was not associated with a dramatic alteration in transcripts encoding either Igf1 or Lpl , indicating that cystatin F may not contribute to remyelination by modulation of remyelination-associated gene expression. More recently, remyelination in JHMV-infected mice has been shown to be related to efficient phagocytosis of myelin debris, and microglia appear to be critical in this process [ 28 , 36 , 50 ]. In the absence of Cst7 expression in JHMV-infected mice, there was an increase in expression of transcripts associated with myeloid cell phagocytosis/lipid metabolism, including Apoe , Trem2 , and Cd36 , in the Cst7-/- mice compared with controls, which argues against impaired myelin phagocytosis by either microglia and/or inflammatory monocytes/macrophages.…”

A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity

“…Dysregulated lipid processing is associated with oxidative and ER stress that alters cell survival and macrophage phenotype (13,(36)(37)(38), which are, in turn, hallmarks of disease progression in type 2 diabetes and Alzheimer's disease (39,40). For example, disease-associated microglia in Alzheimer's disease bear similarity to LAMs and show increased expression of Trem2 ligands Lpl and Apoe (39)(40)(41)(42).…”

Potential therapeutic targets of macrophages in inhibiting immune damage and fibrotic processes in musculoskeletal diseases

“…In neuromuscular system neurodegenerative diseases, the TREM2 receptor on macrophages plays a crucial role in regulating microglial function and neuroinflammation. Mutations or functional defects in TREM2 are closely related to the onset and progression of neurodegenerative diseases (95,185). MARCO interacts with multiple anionic ligands, including nucleic acids, anionic proteins, and lipids, modulating macrophages, inhibiting the activation of natural killer cells and T cells, and increasing the infiltration of regulatory T cells (Tregs), indicating its suppressive function in the immune microenvironment (96,186).…”