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Neutrophil infiltration during inflammation is regulated by PILRα via modulation of integrin activation

Abstract

Acute inflammatory responses are important in host defense, whereas dysregulated inflammation results in life-threatening complications. Here we found that paired immunoglobulin-like type 2 receptor alpha (PILRα), an inhibitory receptor containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs), negatively regulated neutrophil infiltration during inflammation. Pilra−/− mice had increased neutrophil recruitment to inflammatory sites and were highly susceptible to endotoxin shock. Pilra−/− neutrophils showed enhanced transmigration ability and increased adhesion to the β2 integrin ligand ICAM-1. PILRα expressed on neutrophils constitutively associated in cis with its ligands, resulting in clustering of PILRα during stimulation with a chemoattractant. Clustering of PILRα enhanced ITIM-mediated signaling, thus modulating β2 integrin inside-out activation. These data demonstrate that neutrophil recruitment in inflammatory responses is regulated by PILRα via modulation of integrin activation.

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Figure 1: Increased mortality and higher neutrophil infiltration in LPS-induced lethal shock in Pilra−/− mice.
Figure 2: Pilra−/− mice have increased neutrophil recruitment in thioglycollate-induced peritonitis.
Figure 3: Pilra−/− neutrophils have enhanced responses to chemotactic factors.
Figure 4: PILRα associates with ligands in cis on neutrophils.
Figure 5: Interactions of PILRα and cis ligands modulate neutrophil integrin inside-out activation after chemoattractant stimulation.
Figure 6: PILRα aggregates at the leading edge of polarized neutrophils.
Figure 7: SHP-1 redistribution in activated neutrophils is mediated by PILRα.

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Acknowledgements

We thank M. Matsumoto, K. Shida and R. Hirohata for technical assistance, T. Suenaga, M. Kohyama, K. Hirayasu and F. Saito for discussions, and M. Okabe, A. Kawai and M. Tanaka for advice and technical assistance with the generation of the gene-targeted mice. This work was supported by research grants from JST, CREST, a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and The Osaka Foundation for Promotion of Clinical Immunology (H.A.).

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J.W. and H.A. designed the experiments, analyzed the data and wrote the manuscript. J.W. did most of the experiments. I.S., J.U. and M.I. generated Pilra−/− mice. I.S. established a mAb to PILRα.

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Correspondence to Hisashi Arase.

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The authors declare no competing financial interests.

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Wang, J., Shiratori, I., Uehori, J. et al. Neutrophil infiltration during inflammation is regulated by PILRα via modulation of integrin activation. Nat Immunol 14, 34–40 (2013). https://doi.org/10.1038/ni.2456

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