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HIF-alpha signaling mediates the macrophage inflammatory response during Leishmania majorinfection

ABSTRACT: Cutaneous leishmaniasis (CL) is responsible for a significant burden of the global incidence of neglected tropical diseases, with 12 million people currently infected with Leishmania parasites. CL contains a spectrum of disease manifestations, ranging from self-healing skin lesions to permanent disfigurations. Currently there is no vaccine available, and many patients are refractory to treatment, emphasizing the need for new therapeutic targets. Previous work has demonstrated the necessity of macrophage HIF-alpha-mediated lymphangiogenesis to achieve efficient wound resolution during murine L. major infection. Here we investigate the role of macrophage HIF-alpha signaling separate from lymphangiogenesis, employing RNA-Seq transcriptome analysis on macrophages with intact or compromised HIF-alpha signaling, LysMCreARNTf/+ or LysMCreARNTf/f respectively, during L. major infection and under pro-inflammatory stimulus. We report that L. major infection alone is enough to induce HIF-alpha dependent transcriptomic changes while infection with L. major and pro-inflammatory stimuli administration instigates transcriptomic changes both dependent and independent of HIF-alpha signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found during L. major infection and in a pro-inflammatory environment, HIF-alpha suppresses pathways involved in protein translation such as the ribosome pathway and EIF2 signaling. Together this work supports infection with L. major induces a HIF-alpha transcriptomic program, but only in a pro-inflammatory environment does HIF-alpha suppress protein translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE273822 | GEO | 2024/11/01

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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HIF-alpha signaling mediates the macrophage inflammatory response during Leishmania majorinfection

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