Premium
Hypoxia‐Regulated Autophagic Pathways Mediate Epithelial Defense during Mucosal Inflammation
Author(s) -
Kitzenberg David,
Saeedi Bejan,
Kelly Caleb,
Schwisow Kayla,
Campbell Eric,
Lanis Jordi,
Curtis Valerie,
Glover Louise
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.57.4
Subject(s) - autophagy , microbiology and biotechnology , biology , mitophagy , crosstalk , innate immune system , inflammation , mitochondrion , immune system , signal transduction , intestinal mucosa , inflammatory bowel disease , atg16l1 , immunology , apoptosis , disease , medicine , biochemistry , physics , pathology , optics
Intestinal epithelia provide the primary cellular interface between microbiota and host in the mammalian mucosal ecosystem. As such, epithelia actively participate as innate immune sensors of luminal bacteria that breach this barrier. Defects in epithelial autophagy have been identified in inflammatory bowel disease (IBD). Autophagy, a primordial degradation pathway, is implicated in diverse but interconnected immune responses such as mitochondrial signaling and elimination of invasive bacteria. Improved epithelial mitochondrial function proves protective in IBD, and a functional link between mitochondrial autophagy and bacterial autophagy has recently been established. However, crosstalk between these seemingly disparate processes is poorly characterized, and the regulatory pathways involved in epithelial cell‐intrinsic autophagy remain unknown. Recent work has defined a central role for the hypoxia‐inducible factor HIF in promoting epithelial bioenergetics and antimicrobial defense. Using a ChIP‐on‐chip approach, we identified autophagy as a novel pathway coordinately regulated by HIF, and highlighted a cohort of IBD‐implicated genes involved in the selective autophagy of mitochondria ( mitophagy ) and bacteria ( xenophagy ). Enteropathogen invasion was found to be an inherent driver of epithelial hypoxia and HIF‐depleted epithelia displayed dysregulated mitochondrial energetics and abrogated mitophagic and xenophagic responses. Conditional epithelial HIF‐deficient mice demonstrated increased bacterial dissemination and disease activity following acute invasive bacterial challenge. Moreover, augmentation of HIF‐regulated mitochondrial bioenergetics proved protective in mouse models of colitis. These findings place epithelial HIF as a central orchestrator of mitophagic and xenophagic responses during mucosal inflammation. Support or Funding Information This work was supported by a Crohn's and Colitis Foundation of America Career Development Award (LEG) and National Institute of Health NIDDK R01 grant DK103712 (LEG).