Branched Fatty Acid Esters Of Hydroxy Fatty Acids (fahfas) Protect Against Colitis By Regulating Gut Innate And Adaptive Immune Responses

dc.creatorLee
dc.creatorJennifer; Moraes-Vieira
dc.creatorPedro M.; Castoldi
dc.creatorAngela; Aryal
dc.creatorPratik; Yee
dc.creatorEric U.; Vickers
dc.creatorChristopher; Parnas
dc.creatorOren; Donaldson
dc.creatorCynthia J.; Saghatelian
dc.creatorAlan; Kahn
dc.creatorBarbara B.
dc.date2016
dc.dateout
dc.date2017-11-13T11:32:15Z
dc.date2017-11-13T11:32:15Z
dc.date.accessioned2018-03-29T05:46:59Z
dc.date.available2018-03-29T05:46:59Z
dc.identifierJournal Of Biological Chemistry. Amer Soc Biochemistry Molecular Biology Inc, v. 291, p. 22207 - 22217, 2016.
dc.identifier0021-9258
dc.identifier1083-351X
dc.identifierWOS:000386332600032
dc.identifier10.1074/jbc.M115.703835
dc.identifierhttp://www-jbc-org.ez88.periodicos.capes.gov.br/content/291/42/22207.short
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/326051
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1363057
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionWe recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment. The colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4(+) T cells from syngeneic mice were co-cultured to assess antigen presentation and T cell activation in response to LPS. PAHSA treatment prevented weight loss, improved colitis scores (stool consistency, hematochezia, and mouse appearance), and augmented intestinal crypt Paneth cell bactericidal potency via a mechanism that may involve GPR120. In vitro, PAHSAs attenuated dendritic cell activation and subsequent T cell proliferation and Th1 polarization. The anti-inflammatory effects of PAHSAs in vivo resulted in reduced colonic T cell activation and pro-inflammatory cytokine and chemokine expression. These anti-inflammatory effects appear to be partially GPR120-dependent. We conclude that PAHSA treatment regulates innate and adaptive immune responses to prevent mucosal damage and protect against colitis. Thus, PAHSAs may be a novel treatment for colitis and related inflammation-driven diseases.
dc.description291
dc.description42
dc.description22207
dc.description22217
dc.descriptionNIDDK, National Institutes of Health [RO1 DK043051, P30DK57521, RO1 DK106210]
dc.descriptionJPB Foundation
dc.descriptionLeona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
dc.descriptionFundacao de Amparo a Pesquisa do Estado de Sao Paulo [2014/02218-6, 2011/15682-4, 5T32DK007516-31]
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.languageEnglish
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.publisherBethesda
dc.relationJournal of Biological Chemistry
dc.rightsfechado
dc.sourceWOS
dc.subjectColitis
dc.subjectDefensin
dc.subjectInnate Immunity
dc.subjectLipid
dc.subjectT Helper Cells
dc.subjectAnti-inflammatory Lipids
dc.subjectBranched Fatty Acid Esters Of Hydroxy Fatty Acids
dc.subjectImmune Regulation
dc.subjectPaneth Cell
dc.subjectUlcerative Colitis
dc.titleBranched Fatty Acid Esters Of Hydroxy Fatty Acids (fahfas) Protect Against Colitis By Regulating Gut Innate And Adaptive Immune Responses
dc.typeArtículos de revistas


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