Poster De Conférence Année : 2023

A central contribution of HIF-2α in the nutritional immunity against AIEC

Résumé

In a subgroup of Crohn’s disease patients, AIEC are inefficiently cleared by the host and correlate with the intestinal and systemic inflammatory burden. Iron and fucose are two nutrients described to favor the virulence of AIEC. Hence, host has developed diverse mechanisms to limit nutrient availability to the pathogen, also known as nutritional immunity. We previously reported that the HIF-2α transcription factor is involved in iron uptake in the gut under physiological conditions 1. Based on recent preliminary data, we hypothesized here that HIF-2α could be involved in the nutritional immunity against AIEC by decreasing iron and fucose bioavailability in the gastro-intestinal tract. To address this, we generated conditional knockout mice lacking Hif2α specifically in the intestinal epithelium. We first observed that WT mice infected with LF82 induced a more severe and persistent infection upon gavage with iron or fucose, confirming that these two nutrients are favoring AIEC-induced pathogenesis. Interestingly, upon LF82 infection, KOHIF2αInt presented a decrease in fut2 and ferritin expression compared to WT mice, involved respectively in fucose and iron uptake. Moreover, KOHIF2αInt failed to restrict LF82 infection compared to WT mice (mean of CFU/g feces 4 days post-infection: WT= 1.51x107 vs KO=3.84x1010). Finally, KOHIF2αInt mice developed more severe AIEC-induced colitis compared to WT mice. Altogether, our results suggest that HIF2α is required to reduce iron and fucose bioavailability (increase iron uptake and fucosylation) in order to limit AIEC colonization and associated chronic intestinal inflammation.

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Dates et versions

hal-04977484 , version 1 (05-03-2025)

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  • HAL Id : hal-04977484 , version 1

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Marion Falabrègue, Candice Aurrand, Benoît Chassaing, Jérémy Denizot, Nicolas Barnich, et al.. A central contribution of HIF-2α in the nutritional immunity against AIEC. 25th Anniversary of AIEC discovery, Nov 2023, New-York, United States. ⟨hal-04977484⟩
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