Research ArticleINFLAMMATION

Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation

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Science Immunology  10 May 2019:
Vol. 4, Issue 35, eaav5951
DOI: 10.1126/sciimmunol.aav5951

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Atypical attraction

Neutrophils contribute to inflammatory responses by moving from the circulation into target tissues through a series of chemoattractant-driven steps involving arrest and transmigration. Here, Miyabe et al. use an immune complex–induced arthritis murine model to show that neutrophil arrest requires endothelial expression of the atypical complement C5a receptor 2 (C5aR2) to drive transport of C5a into the vessel lumen, which is required for initiation of C5aR1-driven neutrophil arrest. Expression of the atypical chemokine receptor 1 (ACKR1) on endothelial cells mediates transport of CXCR2 chemokine ligands into the lumen and CXCR2-dependent transendothelial migration of neutrophils. These results clarify a role for “atypical” chemoattractant receptors working in conjunction with classical chemoattractant receptors to drive neutrophil arrest and diapedesis.

Abstract

Chemoattractant-induced arrest of circulating leukocytes and their subsequent diapedesis is a fundamental component of inflammation. However, how tissue-derived chemoattractants are transported into the blood vessel lumen to induce leukocyte entry into tissue is not well understood. Here, intravital microscopy in live mice has shown that the “atypical” complement C5a receptor 2 (C5aR2) and the atypical chemokine receptor 1 (ACKR1) expressed on endothelial cells were required for the transport of C5a and CXCR2 chemokine ligands, respectively, into the vessel lumen in a murine model of immune complex–induced arthritis. Transported C5a was required to initiate C5aR1-mediated neutrophil arrest, whereas transported chemokines were required to initiate CXCR2-dependent neutrophil transdendothelial migration. These findings provide new insights into how atypical chemoattractant receptors collaborate with “classical” signaling chemoattractant receptors to control distinct steps in the recruitment of neutrophils into tissue sites of inflammation.

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