MTORC1-mediated macrophage polarization into M1 Contributes to Ehrlichia-induced sepsis

Abstract

Abstract Macrophages heterogeneity that undergo dynamic changes in phenotype and function as well as reprograming of immune response to multiple intracellular bacterial infections is an important key to understand the host responses to infection. Ehrlichia is an obligate Gram-negative intracellular bacterium that cause potentially fatal human monocytotropic ehrlichiosis (HME). We utilized murine models of mild and fatal ehrlichiosis caused by Ehrlichia muris and Ixodes Ovatus Ehrlichia (IOE), respectively, to evaluate the macrophages polarization to inflammatory (M1) and regenerative (M2). Our data show that in vivo and in vitro infections of macrophages with IOE significantly polarize macrophages towards M1, while EM infection enhances M2 polarization. M1 polarization of macrophages in IOE-infected mice was associated with recruitment and/or expansion of granzyme B+ neutrophils, NK cells, IL-17+ NKT cells, and IL-17+ CD4 Th17 cells compared to EM infection. We previously identified mTORC1 (mammalian target of rapamycin complex-1), a negative regulator of autophagy and the key mediator for immunopathology during IOE infection. We found that M1 polarization in the livers of IOE-infected mice is dependent on mTORC1 activation. Blockade of mTORC1 activation with rapamycin decreased frequency of Th17, and enhanced autophagy, which in turn decreased inflammation as well as the pathogenic immune response during lethal IOE infection. Together, these data reveal a key role of mTORC1 in M1 polarization of macrophages, which likely promotes Ehrlichia-induced sepsis. Understanding the dynamic changes of macrophage polarization and how it affects immune responses to infection is crucial for development novel therapeutic strategies.