HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury.
HIF-1α induces glycolytic reprograming in tissue-resident alveolar macrophages to promote cell survival during acute lung injury.
复制标题
缺氧诱导因子-1α（HIF-1α）可诱导组织驻留型肺泡巨噬细胞发生糖酵解重编程，从而在急性肺损伤期间促进细胞存活。
DOI：
10.7554/elife.77457
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发表时间：
2022-07-13
期刊：
影响因子：
7.7
通讯作者：
Mutlu, Goekhan M.
中科院分区：
文献类型：
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作者：
Woods, Parker S.;Kimmig, Lucas M.;Sun, Kaitlyn A.;Meliton, Angelo Y.;Shamaa, Obada R.;Tian, Yufeng;Cetin-Atalay, Renguel;Sharp, Willard W.;Hamanaka, Robert B.;Mutlu, Goekhan M.
Cellular metabolism is a critical regulator of macrophage effector function. Tissue-resident alveolar macrophages (TR-AMs) inhabit a unique niche marked by high oxygen and low glucose. We have recently shown that in contrast to bone marrow-derived macrophages (BMDMs), TR-AMs do not utilize glycolysis and instead predominantly rely on mitochondrial function for their effector response. It is not known how changes in local oxygen concentration that occur during conditions such as acute respiratory distress syndrome (ARDS) might affect TR-AM metabolism and function; however, ARDS is associated with progressive loss of TR-AMs, which correlates with the severity of disease and mortality. Here, we demonstrate that hypoxia robustly stabilizes HIF-1α in TR-AMs to promote a glycolytic phenotype. Hypoxia altered TR-AM metabolite signatures, cytokine production, and decreased their sensitivity to the inhibition of mitochondrial function. By contrast, hypoxia had minimal effects on BMDM metabolism. The effects of hypoxia on TR-AMs were mimicked by FG-4592, a HIF-1α stabilizer. Treatment with FG-4592 decreased TR-AM death and attenuated acute lung injury in mice. These findings reveal the importance of microenvironment in determining macrophage metabolic phenotype and highlight the therapeutic potential in targeting cellular metabolism to improve outcomes in diseases characterized by acute inflammation.
