Two populations of alternatively activated M2 macrophages (TLR4+ vs. Tim-3+) regulate inflammation and fibrosis in the heart during coxsackievirus-induced myocarditis (137.20)

Abstract

Abstract Previously we showed that Toll-like receptor 4 (TLR4) and T cell Ig mucin-3 (Tim-3) cross-regulate each others expression on CD11b+ cells, with TLR4 increasing and Tim-3 reducing cardiac inflammation. We show here that TLR4 and Tim-3 are expressed on GR1+F4/80+IL-4R+ alternatively activated M2 macrophages from the heart during acute myocarditis, but are not expressed on GR1-F4/80+IL-4R- classically activated M1 macrophages. GR1+ cells also express the mannose receptor (CD206), caspase-1, IL-1β and IL-10. In gonadectomized male mice, M2 cells express significantly more Tim-3 and significantly less IL-1β with significantly reduced inflammation. In contrast, complement receptor 1/2 (CR1/2) deficient mice have a significantly increased TLR4+casp-1+IL-1β+ M2 population. Elevated expression of IL-1β by M2 macrophages in the heart leads to significantly increased myocarditis, fibrosis and heart failure in CR1/2 deficient mice. These data indicate that different M2 populations have contrasting roles on the development of heart disease: TLR4+casp-1+IL-1β+ M2 are associated with increased inflammation and fibrosis, while Tim-3+ M2 with decreased inflammation. Deciphering how M2 macrophage populations interact with autoreactive cells and antibodies will be critical in understanding the pathogenesis of autoimmune disease. Supported by NIH grants R01 HL087033 (DF) and R01 HL67290 (NRR).