Abstract
We 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.
Original language | American English |
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Pages (from-to) | 22207-22217 |
Number of pages | 11 |
Journal | Journal of Biological Chemistry |
Volume | 291 |
Issue number | 42 |
DOIs | |
State | Published - 14 Oct 2016 |
Bibliographical note
Funding Information:This work was supported by NIDDK, National Institutes of Health GrantsRO1 DK043051 and P30DK57521 (to B. B. K.) and RO1 DK106210 (to B. B. K. and A. S.), a grant from the JPB Foundation (to B. B. K.), Leona M. and Harry B. Helmsley Charitable Trust Grant 2012-PG-MED002 (to A. S.), Fundação de Amparo a Pesquisa do Estado de São Paulo 2014/02218-6 and 2011/15682-4 (to A. C.), and 5T32DK007516-31 (to B. B. K. and J. L.). B. B. K., A. S., and P. V. are inventors on a patent and patent applications related to the fatty acid hydroxy fatty acids. J. L. is an inventor on a patent application related to the lipids. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.