mTORC1 and mTORC2 selectively regulate macrophage differentiation

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): mTORC1 and mTORC2 selectively regulate macrophage differentiation. Rapid and robust inflammatory responses play a critical role in protecting the host against infections and environmental insults. Likewise, the early induction of negative feedback loops promotes healing and prevents autoimmunity and tissue destruction due to over exuberant responses. Chronic persistent unregulated inflammation often leads to tissue destruction by promoting the development of fibrosis. Although pulmonary fibrosis appears to be the end result of chronic unremitting immune activation, often neither the inciting agents nor the precise factors driving the fibrotic response are known. Macrophages play a crucial role in directing both host-innate and acquired immune responses. Classically activated macrophages (CAM) are induced by IFN-? or LPS and skew the immune response toward a Th1 environment. Alternatively activated macrophages (AAM) are induced by IL-4 or IL-13 and promote a Th2 environment. AAM macrophages have been implicated in both physiologic and pathologic processes such as homeostasis, inflammation, cancer and fibrosis. However, the precise role and even phenotypic definition of alternatively activated macrophage subsets in modulating diseases remains unclear. While it is clear that the environment influences the development of macrophages along a CAM (IFN- ?) or AAM (IL-4) pathway, the precise signaling mechanisms regulating this differentiation remains largely unknown. Recently our collaborator (Jonathan Powell) has determined that the serine/threonine kinase mTOR plays a critical role in directing T helper cell differentiation. T cells lacking mTOR complex 1 (TORC1) selectively fail to develop into Th1 and Th17 cells while T cells lacking TORC2 activity fail to develop into Th2 cells but retain their ability to become Th1 and Th17 cells. We hypothesize that similar to T cell differentiation, macrophage differentiation is also controlled by mTOR. To test this hypothesis, our lab has generated a novel mouse model in which mTOR, mTORC1, or mTORC2 are selectively knocked out in murine macrophages. Indeed our preliminary data support this hypothesis and further delineate a critical role for mTOR in macrophages in regulating the inflammation leading to pulmonary fibrosis. To this end we will test the hypothesis that mTOR plays a critical role in the development of alternatively activated macrophages and pulmonary fibrosis by pursuing the following Specific Aims: Aim 1 - mTOR regulates macrophage differentiation and Aim 2 - alternatively activated macrophages (M2) promote pulmonary fibrosis.