Restraint of Fumarate Accrual by HIF-1α Preserves miR-27a-Mediated Limitation of Interleukin 10 during Infection of Macrophages by Histoplasma capsulatum.
Restraint of Fumarate Accrual by HIF-1α Preserves miR-27a-Mediated Limitation of Interleukin 10 during Infection of Macrophages by Histoplasma capsulatum.
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DOI：
10.1128/mbio.02710-21
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发表时间：
2021-12-21
期刊：
影响因子：
6.4
通讯作者：
Deepe GS Jr
中科院分区：
文献类型：
--
作者：
Evans HM;Schultz DF;Boiman AJ;McKell MC;Qualls JE;Deepe GS Jr
缺氧诱导因子 1α (HIF-1α) 调节巨噬细胞的免疫代谢表型，包括协调炎症和抗菌过程。缺乏 HIF-1α 的巨噬细胞在感染细胞内真菌病原体荚膜组织胞浆菌时会产生过量的抗炎细胞因子白细胞介素 10 (IL-10) (R. A. Fecher, M. C. Horwath, D. Friedrich, J. Rupp, G. S. Deepe, J Nutrition 197:565–579, 2016, https://doi.org/10.4049/jimmunol.1600342）。因此，巨噬细胞无法响应促炎细胞因子而被激活，并且仍然是病原体的细胞内生态位。在这里，我们确定在缺乏 HIF-1α 的情况下，在荚膜梭菌感染巨噬细胞期间，三羧酸 (TCA) 循环代谢物富马酸是 IL-10 的驱动因素。富马酸盐的积累会降低 HIF-1α 依赖性 microRNA (miRNA) miR-27a 的表达，miR-27a 已知可介导 Il10 mRNA 的衰减。体内富马酸累积的抑制限制了 IL-10 和真菌生长。我们的数据证明了 HIF-1α 在塑造适当的 TCA 循环活性以应对感染方面的关键作用，并强调了免疫代谢反应失调的后果。
Hypoxia-inducible factor 1α (HIF-1α) regulates the immunometabolic phenotype of macrophages, including the orchestration of inflammatory and antimicrobial processes. Macrophages deficient in HIF-1α produce excessive quantities of the anti-inflammatory cytokine interleukin 10 (IL-10) during infection with the intracellular fungal pathogen Histoplasma capsulatum (R. A. Fecher, M. C. Horwath, D. Friedrich, J. Rupp, G. S. Deepe, J Immunol 197:565–579, 2016, https://doi.org/10.4049/jimmunol.1600342). Thus, the macrophage fails to become activated in response to proinflammatory cytokines and remains the intracellular niche of the pathogen. Here, we identify the tricarboxylic acid (TCA) cycle metabolite fumarate as the driver of IL-10 during macrophage infection with H. capsulatum in the absence of HIF-1α. Accumulation of fumarate reduced expression of a HIF-1α-dependent microRNA (miRNA), miR-27a, known to mediate decay of Il10 mRNA. Inhibition of fumarate accrual in vivo limited IL-10 and fungal growth. Our data demonstrate the critical role of HIF-1α in shaping appropriate TCA cycle activity in response to infection and highlight the consequences of a dysregulated immunometabolic response.