Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis

Abstract

Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium-targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1-regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.

Hypoxia and gastrointestinal disease

“…Moreover, Vascular endothelial growth factor-dependent angiogenesis appears to be an integral part of human IBD [14]. In support of these hypotheses, studies in murine models have identified the epithelium as the central target of hypoxia during active mucosal inflammation [15]. As part of our ongoing work, we have confirmed the existence of mucosal hypoxia in murine models of IBD using 2-nitroimidazole dyes, a class of compounds known to undergo intracellular metabolism depending on the availability of oxygen within tissue (Fig.…”

“…Accumulation of nitroimidazole adducts, particularly in the epithelium, were as intense as those observed in some tumors, suggesting the existence of intense foci of hypoxia associated with these inflammatory lesions. While we do not yet know the basis for such inflammatory hypoxia, some evidence suggests that tissue vasculitis could predispose epithelia toward diminished oxygen delivery [15].…”

“…To more fully understand the physiologic implications of intestinal epithelial HIF, Karhausen et al [15] generated two mouse lines with intestinal epithelial-targeted expression of either mutant Hif1a (constitutive repression of HIF-1) or mutant von Hippel-Lindau gene (Vhlh, constitutive overexpression of HIF, which includes HIF-1 and HIF-2). Studies of colitis in these mice revealed that the loss of epithelial HIF-1 correlated with more severe clinical symptoms (mortality, weight loss, colon length, intestinal epithelial permeability), whereas an increase in epithelial HIF was protective for these individual parameters.…”

“…Reactions conducted in a limited oxygen environment have revealed that the activity of the purified enzyme is strikingly sensitive to diminished levels of oxygen in vitro [26][27]. The three enzymes have different tissue distributions and, at least under conditions of overexpression, have distinct patterns of subcellular localization [15,19]. PHD1 mRNA is expressed in many tissues, with especially high expression in the testis.…”

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

“…Peripheral tissues, even under homeostatic conditions, are characterized by site-specific low oxygen tension, and O 2 availability is further limited in the context of injury/inflammation, with increased O 2 consumption by infiltrating immune cells, and swelling/edema heightening the distance to the nearest blood vessel (3)(4)(5)(6)(7).…”