| First Author | Zen K | Year | 2013 |
| Journal | Nat Commun | Volume | 4 |
| Pages | 2436 | PubMed ID | 24026300 |
| Mgi Jnum | J:263441 | Mgi Id | MGI:6189453 |
| Doi | 10.1038/ncomms3436 | Citation | Zen K, et al. (2013) Inflammation-induced proteolytic processing of the SIRPalpha cytoplasmic ITIM in neutrophils propagates a proinflammatory state. Nat Commun 4:2436 |
| abstractText | Signal regulatory protein alpha (SIRPalpha), an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, is an essential negative regulator of leukocyte inflammatory responses. Here we report that SIRPalpha cytoplasmic signalling ITIMs in neutrophils are cleaved during active inflammation and that the loss of SIRPalpha ITIMs enhances the polymorphonuclear leukocyte (PMN) inflammatory response. Using human leukocytes and two inflammatory models in mice, we show that the cleavage of SIRPalpha 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 SIRPalpha but lacking the ITIMs. Moreover, the loss of SIRPalpha ITIMs in PMNs during colitis is blocked by an anti-interleukin-17 (IL-17) antibody. These results demonstrate a SIRPalpha-based mechanism that dynamically regulates PMN inflammatory responses by generating a CD47-binding but non-signalling SIRPalpha 'decoy'. |
