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

• Published in: The Journal of immunology (1950) 2015-08, Vol.195 (3), p.1139-1151
• Main Authors: McArthur, Simon, Gobbetti, Thomas, Kusters, Dennis H M, Reutelingsperger, Christopher P, Flower, Roderick J, Perretti, Mauro
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Animals; Annexin A1 - genetics; Annexin A1 - immunology; Apoptosis - immunology; Cells, Cultured; Enzyme Activation - immunology; Humans; Inflammation - immunology; Innate Immunity and Inflammation; Lipopolysaccharide Receptors - metabolism; Lysophospholipids - biosynthesis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes - immunology; Neutrophils - immunology; Neutrophils - transplantation; p38 Mitogen-Activated Protein Kinases - metabolism; Phospholipases A2, Calcium-Independent - metabolism; Receptors, Formyl Peptide - biosynthesis; Receptors, Formyl Peptide - genetics; Receptors, Formyl Peptide - metabolism; Receptors, IgG - metabolism; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - immunology; RNA Interference; RNA, Small Interfering; Zymosan
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500733

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.