Browsing Upstate Medical University by Subject "virus-induced"
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SHP-1-dependent macrophage responses mediate virus-induced myositis and demyelinating disease.Regulation of inflammatory immune responses to pathogenic microbial infections is critical for protecting against extensive tissue damage and chronic inflammation. Correspondingly, genes associated with inflammatory immune responses have been identified as potential genetic risk factors for chronic inflammatory diseases including multiple sclerosis (MS) and idiopathic inflammatory myopathies (IIMs). This dissertation will focus on characterizing how the key immune regulator, Src-homology 2 containing protein tyrosine phosphatase-1 (SHP-1), controls virus-induced inflammatory diseases in the central nervous system (CNS) and skeletal muscle. We previously reported that SHP-1 inhibits proinflammatory macrophage-mediated CNS demyelinating disease during Theiler’s murine encephalomyelitis (TMEV) infection in mice. Presently, we describe that SHP-1 controls TMEV-induced dystrophic calcification of skeletal muscle. Muscle-infiltrating macrophages displayed a proinflammatory M1-like phenotype and promoted muscle calcification in WT mice, whereas an increased infiltration of macrophages with a reduced M1 signature corresponded with absence of muscle disease in SHP-1-/-mice. These studies reveal SHP-1 as a key regulatory gene mediating CNS and skeletal muscle disease in response to a virus trigger.Proinflammatory macrophages promoted tissue damage in either skeletal muscle of WT mice or CNS of SHP-1-deficient mice following TMEV infection. We thus attempted to determine if SHP-1 activity within macrophages was sufficient to control the outcome of TMEV infection using multiple genetic approaches. However, since these cells have a high turnover rate, and SHP-1 was strongly induced in macrophages by TMEV infection, these approaches were not sufficient to address whether SHP-1 activity specifically within macrophages mediates tissue-specific disease outcomes following TMEV infection. The studies described here suggest that SHP-1 affects macrophage maturation in peripheral (muscle) and immune-privileged (CNS) tissues in opposite ways. However, SHP-1 inhibited inflammatory monocyte CCR2 expression and subsequent infiltration into both of these major sites of infection, indicating that additional environmental cues mediated by SHP-1 are needed to drive tissue-specific maturation of pathogenic M1-like macrophages in either the CNS or muscle, to explain tissue-specific disease outcomes in SHP-1-deficient mice. Thus, this dissertation characterized unique mechanisms by which SHP-1 mediates inflammatory responses to virus infections, and has revealed SHP-1 and proinflammatory M1-like macrophages as essential mediators of myositis and demyelinating CNS disease.