Non-Lyn Src Family Kinases Activate SIRPα-SHP-1 to Inhibit PI3K-Akt2 and Dampen Proinflammatory Macrophage Polarization.

ABSTRACT: Macrophage functional plasticity plays a central role in responding to proinflammatory stimuli. The molecular basis underlying the dynamic phenotypic activation of macrophages, however, remains incompletely understood. In this article, we report that SIRPα is a chief negative regulator of proinflammatory macrophage polarization. In response to TLR agonists, proinflammatory cytokines, or canonical M1 stimulation, Src family kinases (SFK) excluding Lyn phosphorylate SIRPα ITIMs, leading to the preferential recruitment and activation of SHP-1, but not SHP-2. Solely extracellular ligation of SIRPα by CD47 does not greatly induce phosphorylation of SIRPα ITIMs, but it enhances proinflammatory stimuli-induced SIRPα phosphorylation. Examination of downstream signaling elicited by IFN-γ and TLR3/4

SUBMITTER: Shi L 

PROVIDER: S-EPMC8387419 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature