title: Arginase activity in alternatively activated macrophages protects PI3Kp110δ deficient mice from dextran sodium sulfate induced intestinal inflammation.
abstract: Alternatively activated or M2 macrophages have been reported to protect mice from intestinal inflammation, but the mechanism of protection has not been elucidated. In this study, we demonstrate that mice deficient in the p110δ catalytic subunit activity of class I phosphatidylinositol 3-kinase (PI3Kp110δ) have increased clinical disease activity and histological damage during dextran sodium sulfate (DSS) induced colitis. Increased disease severity in PI3Kp110δ-deficient mice is dependent on professional phagocytes and correlates with reduced numbers of arginase I+ M2 macrophages in the colon and increased production of inflammatory nitric oxide. We further demonstrate that PI3Kp110δ-deficient macrophages are defective in their ability to induce arginase I when skewed to an M2 phenotype with IL-4. Importantly, adoptive transfer of IL-4-treated macrophages derived from WT mice, but not those from PI3Kp110δ-deficient mice, protects mice during DSS-induced colitis. Moreover, M2 macrophages mediated protection is lost when mice are cotreated with inhibitors that block arginase activity or during adoptive transfer of arginase I deficient M2 macrophages. Taken together, our data demonstrate that arginase I activity is required for M2 macrophages mediated protection during DSS-induced colitis in PI3Kp110δ-deficient mice.
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child & Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Weisser
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Kozicky
authors.forename: Hayley K
authors.initials: HK
authors.lastname: Brugger
authors.forename: Eyler N
authors.initials: EN
authors.lastname: Ngoh
authors.forename: Bonnie
authors.initials: B
authors.lastname: Cheung
authors.forename: Roger
authors.initials: R
authors.lastname: Jen
authors.forename: Susan C
authors.initials: SC
authors.lastname: Menzies
authors.forename: Asanga
authors.initials: A
authors.lastname: Samarakoon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: C James
authors.initials: CJ
authors.lastname: Lim
authors.forename: Pauline
authors.initials: P
authors.lastname: Johnson
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Boucher
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D058534:Class I Phosphatidylinositol 3-Kinases; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics*
chemical_list: D001119:Arginase; D058534:Class I Phosphatidylinositol 3-Kinases; D016264:Dextran Sulfate; D015847:Interleukin-4; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; C544448:Arg1 protein, mouse
keywords: Alternatively activated macrophages; Arginase; Colitis; DSS-induced intestinal inflammation; PI3Kp110δ