mTORC1 and mTORC2 selectively regulate macrophage differentiation

描述(申请人提供)：mTORC1和mTORC2选择性地调节巨噬细胞分化。快速而有力的炎症反应在保护宿主免受感染和环境侮辱方面起着至关重要的作用。同样，早期负反馈环的诱导促进了愈合，并防止了由于过度兴奋的反应而导致的自身免疫和组织破坏。慢性持续性非调节性炎症往往通过促进纤维化的发展而导致组织破坏。虽然肺纤维化似乎是慢性持续免疫激活的最终结果，但通常既不知道刺激因素，也不知道驱动纤维化反应的确切因素。巨噬细胞在引导宿主的先天免疫反应和获得性免疫反应中起着至关重要的作用。经典激活的巨噬细胞(CAM)是由干扰素？或内毒素，并使免疫反应向Th1环境倾斜。另一种激活的巨噬细胞(AAM)由IL-4或IL-13诱导，并促进Th2环境。AAM巨噬细胞参与了体内平衡、炎症、癌症和纤维化等生理和病理过程。然而，“交替激活”巨噬细胞亚群在调节疾病中的确切作用甚至表型定义仍不清楚。显然，环境影响巨噬细胞沿CAM(干扰素？)的发育。或AAM(IL-4)途径，调控这种分化的确切信号机制在很大程度上仍不清楚。最近，我们的合作者乔纳森·鲍威尔(Jonathan Powell)确定，丝氨酸/苏氨酸激酶mTOR在引导辅助性T细胞分化方面发挥着关键作用。缺乏mTOR复合体1(TORC1)的T细胞选择性地不能发育成Th1和Th17细胞，而缺乏TORC2活性的T细胞不能发育成Th2细胞，但仍有能力成为Th1和Th17细胞。我们推测，与T细胞分化类似，巨噬细胞的分化也受mTOR控制。为了验证这一假设，我们的实验室建立了一种新的小鼠模型，在该模型中，mTOR、mTORC1或mTORC2在小鼠巨噬细胞中被选择性地敲除。事实上，我们的初步数据支持这一假说，并进一步描述了巨噬细胞中mTOR在调节导致肺纤维化的炎症中的关键作用。为此，我们将通过追求以下特定目的来验证mTOR在交替激活的巨噬细胞和肺纤维化的发展中起关键作用的假设：目的1-mTOR调节巨噬细胞的分化，目的2-交替激活的巨噬细胞(M2)促进肺纤维化。

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.