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 TLR3/4/9 agonists found that SIRPα-activated SHP-1 moderately represses STAT1, NF-κB, and MAPK signaling but markedly inhibits Akt2, resulting in dampened proinflammatory cytokine production and expression of Ag presentation machinery. Pharmacological inhibition of SHP-1 or deficiency of SIRPα conversely attenuates SIRPα-mediated inhibition and, as such, augments macrophage proinflammatory polarization that in turn exacerbates proinflammation in mouse models of type I diabetes and peritonitis. Our results reveal an SFK–SIRPα–SHP-1 mechanism that fine-tunes macrophage proinflammatory phenotypic activation via inhibition of PI3K–Akt2, which controls the transcription and translation of proinflammatory cytokines, Ag presentation machinery, and other cellular programs. Key Points SIRPα controls TLR agonist– and IFN-γ–induced macrophage proinflammatory activation. SIRPα deficiency exacerbates type I diabetes and peritonitis in mice. SFK(s), but not Lyn, phosphorylate SIRPα to recruit SHP-1 in proinflammatory states.