Definition of a Novel Pathway Centered on Lysophosphatidic Acid To Recruit Monocytes during the Resolution Phase of Tissue Inflammation

Simon McArthur*, Thomas Gobbetti, Dennis H. M. Kusters, Christopher P. Reutelingsperger, Roderick J. Flower, Mauro Perretti

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

46 Citations (Web of Science)

Abstract

Blood-derived monocytes remove apoptotic cells and terminate inflammation in settings as diverse as atherosclerosis and Alzheimer's disease. They express high levels of the proresolving receptor ALX/FPR2, which is activated by the protein annexin A1 (ANXA1), found in high abundance in inflammatory exudates. Using primary human blood monocytes from healthy donors, we identified ANXA1 as a potent CD14(+)CD16(-) monocyte chemoattractant, acting via ALX/FPR2. Downstream signaling pathway analysis revealed the p38 MAPK-mediated activation of a calcium independent phospholipase A(2) with resultant synthesis of lysophosphatidic acid (LPA) driving chemotaxis through LPA receptor 2 and actin cytoskeletal mobilization. In vivo experiments confirmed ANXA1 as an independent phospholipase A(2)-dependent monocyte recruiter; congruently, monocyte recruitment was significantly impaired during ongoing zymosan-induced inflammation in AnxA1(-/-) or alx/fpr2/3(-/-) mice. Using a dorsal airpouch model, passive transfer of apoptotic neutrophils between AnxA1(-/-) and wild-type mice identified effete neutrophils as the primary source of soluble ANXA1 in inflammatory resolution. Together, these data elucidate a novel proresolving network centered on ANXA1 and LPA generation and identify previously unappreciated determinants of ANXA1 and ALX/FPR2 signaling in monocytes.
Original languageEnglish
Pages (from-to)1139-1151
JournalJournal of Immunology
Volume195
Issue number3
DOIs
Publication statusPublished - 1 Aug 2015

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