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 TNBS 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 to 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 IL-1β, IL-6 and 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 the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis.

Oxygen metabolism and barrier regulation in the intestinal mucosa

“…and likewise demonstrate significant protection in colitis models (14,137,138). Results from these studies in preclinical models indicate that GI diseases may be one of the more promising applications for PHD inhibitor-based therapies.…”

PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function

“…Of the three PHDs (PHD1-3), PHD2 appears to be the primary one that contributes the majority of prolyl hydroxylase activity (26,38), and PHD3 is more effective in suppression of HIF-2␣ (39). A few studies showed that HIF-1␣ prevented mice from intestinal inflammation (31,40,41). In contrast, HIF-2␣ was found to activate the inflammatory response in the intestinal epithelium and promote mice colitis (32).…”

Anthrax Lethal Toxin Inhibits Translation of Hypoxia-inducible Factor 1α and Causes Decreased Tolerance to Hypoxic Stress

“…Multiple reports have indicated a critical role for HIF-1␣ in promoting the survival of cardiomyocytes in hypoxic environments (44,45), suggesting that inhibition of HIF-1␣ may contribute to the cardiomyocyte degeneration that has been shown in LT-treated mice (12). The HIF-1␣ translation blockade could also play a role in establishing and maintaining infection by acting on barrier cells, as HIF-1␣ is critical for limiting the damage to the mucosal barrier under stress conditions (46,47). Moreover, the HIF-1␣ translation blockade could alter host immune responses to infection, as HIF-1␣ regulates the function of both innate and adaptive immunity (48 -52).…”