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

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 (PILR alpha), 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 beta(2) integrin ligand ICAM-1. PILR alpha expressed on neutrophils constitutively associated in cis with its ligands, resulting in clustering of PILR alpha during stimulation with a chemoattractant. Clustering of PILR alpha enhanced ITIM-mediated signaling, thus modulating beta(2) integrin inside-out activation. These data demonstrate that neutrophil recruitment in inflammatory responses is regulated by PILR alpha via modulation of integrin activation.