Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state

Ke Zen, Yalan Guo, Zhen Bian, Zhiyuan Lv, Dihan Zhu, Hiroshi Ohnishi, Takashi Matozaki and Yuan Liu ()
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Ke Zen: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences
Yalan Guo: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences
Zhen Bian: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences
Zhiyuan Lv: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences
Dihan Zhu: Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences
Hiroshi Ohnishi: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University
Takashi Matozaki: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University
Yuan Liu: Center for Inflammation, Immunity and Infection, Georgia State University, PO Box 4010, Atlanta, Georgia 30303, USA

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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’.

Date: 2013
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DOI: 10.1038/ncomms3436

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