title: Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis.
abstract: Pharmacological stabilization of hypoxia-inducible factor (HIF) through prolyl hydroxylase (PHD) inhibition limits mucosal damage associated with models of murine colitis. However, little is known about how PHD inhibitors (PHDi) influence systemic immune function during mucosal inflammation or the relative importance of immunological changes to mucosal protection. We hypothesized that PHDi enhances systemic innate immune responses to colitis-associated bacteremia. Mice with colitis induced by trinitrobenzene sulfonic acid were treated with AKB-4924, a new HIF-1 isoform-predominant PHDi, and clinical, immunological, and biochemical endpoints were assessed. Administration of AKB-4924 led to significantly reduced weight loss and disease activity compared with vehicle controls. Treated groups were pyrexic but did not become subsequently hypothermic. PHDi treatment augmented epithelial barrier function and led to an approximately 50-fold reduction in serum endotoxin during colitis. AKB-4924 also decreased cytokines involved in pyrogenesis and hypothermia, significantly reducing serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10. Treatment offered no protection against colitis in epithelial-specific HIF-1α-deficient mice, strongly implicating epithelial HIF-1α as the tissue target for AKB-4924-mediated protection. Taken together, these results indicate that inhibition of prolyl hydroxylase with AKB-4924 enhances innate immunity and identifies that the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis.
authors.affiliation: 1] School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia [2] Hunter Medical Research Institute, John Hunter Hospital, New South Wales, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Keely
authors.affiliation: Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Campbell
authors.affiliation: School of Veterinary Medicine, University College Dublin, Dublin, Ireland.
authors.forename: A W
authors.initials: AW
authors.lastname: Baird
authors.affiliation: 1] School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia [2] Hunter Medical Research Institute, John Hunter Hospital, New South Wales, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Shalwitz
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kotsakis
authors.affiliation: Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: E N
authors.initials: EN
authors.lastname: McNamee
authors.affiliation: Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kominsky
authors.affiliation: Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy; D005260:Female; D051793:Hypoxia-Inducible Factor 1 / Q000819:agonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D018928:Immunity, Mucosal / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D010539:Permeability / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C575838:AKB-4924; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010879:Piperazines; D064800:Prolyl-Hydroxylase Inhibitors; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D064828:Prolyl Hydroxylases