title: Definition of a Novel Pathway Centered on Lysophosphatidic Acid To Recruit Monocytes during the Resolution Phase of Tissue Inflammation.
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 A2 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 A2-dependent monocyte recruiter; congruently, monocyte recruitment was significantly impaired during ongoing zymosan-induced inflammation in AnxA1(-/-) or alx/fpr2/3(-/-) mice. Using a dorsal air-pouch 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.
authors.affiliation: William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom; s.mcarthur@westminster.ac.uk m.perretti@qmul.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: McArthur
authors.affiliation: William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom;
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.affiliation: CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, the Netherlands; and Department of Biochemistry, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Dennis H M
authors.initials: DH
authors.lastname: Kusters
authors.affiliation: CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, the Netherlands; and Department of Biochemistry, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Reutelingsperger
authors.affiliation: William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom;
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Flower
authors.affiliation: William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom; s.mcarthur@westminster.ac.uk m.perretti@qmul.ac.uk.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008246:Lysophospholipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000637:transplantation; D054512:Phospholipases A2, Calcium-Independent / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000276:immunology*; D015054:Zymosan; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017305:Annexin A1; D018950:Lipopolysaccharide Receptors; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D044042:Receptors, Formyl Peptide; D017452:Receptors, IgG; D049368:Receptors, Lysophosphatidic Acid; C573274:annexin A1, mouse; C481578:formyl peptide receptor 2, mouse; D015054:Zymosan; D048051:p38 Mitogen-Activated Protein Kinases; D054512:Phospholipases A2, Calcium-Independent; C032881:lysophosphatidic acid