title: PLA2G5 regulates transglutaminase activity of human IL-4-activated M2 macrophages through PGE2 generation.
abstract: Phospholipases A2 are enzymes that liberate membrane-bound lipids in a tissue and cell-specific fashion. Group V secretory phospholipase A2 is necessary for the development of M2 macrophages and their effector functions in a mouse model of the T-helper-2 allergic airway inflammation. However, the function of group V phospholipase A2 in human M2 activation and T-helper-2 inflammation is ill-defined. Transglutaminase-2, a protein cross-linking enzyme, is a newly identified marker of both human and mouse interleukin-4-activated M2 macrophages and is also found in the lungs of patients with asthma. We report that group V phospholipase A2 and transglutaminase-2 colocalized in macrophages of human nasal polyp tissue obtained from patients with T-helper-2 eosinophilic inflammation, and their coexpression positively correlated with the number of eosinophils in each tissue specimen. We demonstrate that in human monocyte-derived macrophages activated by interleukin-4, group V phospholipase A2 translocated and colocalized with transglutaminase-2 in the cytoplasm and on the membrane of macrophages. Moreover, knocking down group V phospholipase A2 with small interfering ribonucleic acid reduced macrophage transglutaminase activity, whereas mass spectrometry analysis of lipids also showed reduced prostaglandin E2 production. Finally, exogenous prostaglandin E2 restored transglutaminase activity of group V phospholipase A2-small interfering ribonucleic acid-treated macrophages. Thus, our study shows a novel function of group V phospholipase A2 in regulating the transglutaminase activity of human interleukin-4-activated M2 macrophages through prostaglandin E2 generation and suggests that group V phospholipase A2 is a functionally relevant enzyme that may have therapeutic value for the treatment of human T-helper-2 inflammatory disorders.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston Massachusetts, USA; and the Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Medicine, Harvard Medical School, Boston Massachusetts, USA; and the Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zacharia
authors.affiliation: Department of Medicine, Harvard Medical School, Boston Massachusetts, USA; and the Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Laidlaw
authors.affiliation: Department of Medicine, Harvard Medical School, Boston Massachusetts, USA; and the Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA bbalestrieri@rics.bwh.harvard.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Balestrieri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054505:Group V Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009298:Nasal Polyps / Q000378:metabolism* / Q000473:pathology; D011503:Transglutaminases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015847:Interleukin-4; D011503:Transglutaminases; D054505:Group V Phospholipases A2; C516299:PLA2G5 protein, human; D015232:Dinoprostone
keywords: TGM2; asthma; eosinophil; inflammation; nasal polyp; phospholipase A2