Fry Lucy G, Washam Charity L, Roys Hayden, Bowlin Anne K, Venugopal Gopinath, Bird Jordan T, Byrum Stephanie D, Weinkopff Tiffany
Department of Microbiology and Immunology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Front Immunol. 2025 Mar 21;16:1487311. doi: 10.3389/fimmu.2025.1487311. eCollection 2025.
Cutaneous leishmaniasis (CL) contributes significantly to the global burden of neglected tropical diseases, with 12 million people currently infected with parasites. CL encompasses a range of disease manifestations, 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 demonstrated macrophage HIF-α-mediated lymphangiogenesis is necessary to achieve efficient wound resolution during murine infection. Here, we investigate the role of macrophage HIF-α signaling independent of lymphangiogenesis. We sought to determine the relative contributions of the parasite and the host-mediated inflammation in the lesional microenvironment to myeloid HIF-α signaling. Because HIF-α activation can be detected in infected and bystander macrophages in leishmanial lesions, we hypothesize it is the host's inflammatory response and microenvironment, rather than the parasite, that triggers HIF-α activation. To address this, macrophages from mice with intact HIF-α signaling (LysMARNT) or mice with deleted HIF-α signaling (LysMARNT) were subjected to RNASequencing after infection and under pro-inflammatory stimulus. We report that infection alone is enough to induce some minor HIF-α-dependent transcriptomic changes, while infection with in combination with pro-inflammatory stimuli induces numerous transcriptomic changes that are both dependent and independent of HIF-α signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found HIF-α suppresses pathways involved in protein translation during infection in a pro-inflammatory environment. Together these findings show induces a HIF-α-dependent transcriptomic program, but HIF-α only suppresses protein translation in a pro-inflammatory environment. Thus, this work indicates the host inflammatory response, rather than the parasite, largely contributes to myeloid HIF-α signaling during infection.
皮肤利什曼病（CL）在被忽视的热带病全球负担中占比重大，目前有1200万人感染寄生虫。CL涵盖一系列疾病表现，从可自愈的皮肤损伤到永久性毁容。目前尚无可用疫苗，许多患者对治疗难治，这凸显了新治疗靶点的必要性。先前的研究表明，巨噬细胞HIF-α介导的淋巴管生成对于小鼠感染期间有效伤口愈合是必要的。在此，我们研究巨噬细胞HIF-α信号传导独立于淋巴管生成的作用。我们试图确定病变微环境中寄生虫和宿主介导的炎症对髓系HIF-α信号传导的相对贡献。由于在利什曼病病变的感染和旁观巨噬细胞中均可检测到HIF-α激活，我们推测是宿主的炎症反应和微环境而非寄生虫触发了HIF-α激活。为解决此问题，对具有完整HIF-α信号传导的小鼠（LysMARNT）或HIF-α信号传导缺失的小鼠（LysMARNT）的巨噬细胞在感染后和促炎刺激下进行RNA测序。我们报告称，仅感染就足以诱导一些轻微的HIF-α依赖性转录组变化，而感染加促炎刺激则诱导大量依赖和独立于HIF-α信号传导的转录组变化。此外，通过将转录组分析与多种途径分析相结合，我们发现HIF-α在促炎环境下感染期间抑制参与蛋白质翻译的途径。这些发现共同表明，感染诱导了HIF-α依赖性转录组程序，但HIF-α仅在促炎环境下抑制蛋白质翻译。因此，这项工作表明，在感染期间，宿主炎症反应而非寄生虫在很大程度上促成了髓系HIF-α信号传导。
