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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. Method Wild type (WT) and 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 a dysregulated inflammatory 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 other demyelination models and supports that Trem2 function is mainly regulated by sensing a dysregulated lipid environment, independent of the initial insult or the inflammatory milieu. |
