HIF-1α is essential for myeloid cell-mediated inflammation
HIF-1α is essential for myeloid cell-mediated inflammation
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DOI：
10.1016/s0092-8674(03)00154-5
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发表时间：
2003-03-07
期刊：
影响因子：
64.5
通讯作者：
Johnson, RS
中科院分区：
文献类型：
--
作者：
Cramer, T;Yamanishi, Y;Johnson, RS
粒细胞和单核细胞/巨噬细胞的髓系是主要的细胞剂的先天免疫。在这里，我们研究了缺氧反应性转录因子HIF-1 α、其负调节因子VHL和已知的下游靶点VEGF的条件性敲除小鼠的炎症反应。我们发现HIF-1 α的激活是髓样细胞浸润和激活所必需的，通过一种独立于VEGF的机制。VHL的缺失导致急性炎症反应的大幅增加。我们的研究结果表明，HIF-1 α是必不可少的调节糖酵解能力的髓样细胞：当HIF-1 α是缺席，细胞ATP池急剧减少。代谢缺陷导致骨髓细胞聚集、运动、侵袭和细菌杀伤的严重损害。HIF-1 α的这种作用表明其在炎症微环境中直接调节生存和功能。
Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.