title: Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state.
abstract: Signal regulatory protein α (SIRPα), an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, is an essential negative regulator of leukocyte inflammatory responses. Here we report that SIRPα cytoplasmic signalling ITIMs in neutrophils are cleaved during active inflammation and that the loss of SIRPα ITIMs enhances the polymorphonuclear leukocyte (PMN) inflammatory response. Using human leukocytes and two inflammatory models in mice, we show that the cleavage of SIRPα 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 SIRPα but lacking the ITIMs. Moreover, the loss of SIRPα ITIMs in PMNs during colitis is blocked by an anti-interleukin-17 (IL-17) antibody. These results demonstrate a SIRPα-based mechanism that dynamically regulates PMN inflammatory responses by generating a CD47-binding but non-signalling SIRPα 'decoy'.
authors.affiliation: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences, Nanjing 210093, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.forename: Yalan
authors.initials: Y
authors.lastname: Guo
authors.forename: Zhen
authors.initials: Z
authors.lastname: Bian
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Lv
authors.forename: Dihan
authors.initials: D
authors.lastname: Zhu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000378:metabolism*; D015153:Blotting, Western; D051928:CD47 Antigen / Q000378:metabolism; D002465:Cell Movement; D002469:Cell Separation; D003593:Cytoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D059748:Proteolysis; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*; D017384:Sequence Deletion; D057057:Serine Proteases / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D057057:Serine Proteases
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