Inflammation-induced proteolytic processing of the SIRP? cytoplasmic ITIM in neutrophils propagates a proinflammatory state.

ABSTRACT: Signal regulatory protein ? (SIRP?), an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, is an essential negative regulator of leukocyte inflammatory responses. Here we report that SIRP? cytoplasmic signalling ITIMs in neutrophils are cleaved during active inflammation and that the loss of SIRP? ITIMs enhances the polymorphonuclear leukocyte (PMN) inflammatory response. Using human leukocytes and two inflammatory models in mice, we show that the cleavage of SIRP? ITIMs in PMNs but not monocytes occurs at the post-acute stage of inflammation and correlates with increased PMN recruitment to inflammatory loci. Enhanced transmigration of PMNs and PMN-associated tissue damage are confirmed in mutant mice expressing SIRP? but lacking the ITIMs. Moreover, the loss of SIRP? ITIMs in PMNs during colitis is blocked by an anti-interleukin-17 (IL-17) antibody. These results demonstrate a SIRP?-based mechanism that dynamically regulates PMN inflammatory responses by generating a CD47-binding but non-signalling SIRP? 'decoy'.

SUBMITTER: Zen K 

PROVIDER: S-EPMC5875419 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature