Pharmacological Inhibition of Glutaminase 1 Attenuates Alkali-Induced Corneal Neovascularization by Modulating Macrophages.
Pharmacological Inhibition of Glutaminase 1 Attenuates Alkali-Induced Corneal Neovascularization by Modulating Macrophages.
复制标题
谷氨酰胺酶 1 的药理抑制作用通过调节巨噬细胞来减弱碱诱导的角膜新生血管形成
DOI：
10.1155/2022/1106313
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发表时间：
2022
影响因子：
--
通讯作者：
Yuan F
中科院分区：
文献类型：
--
作者：
Feng Y;Yang X;Huang J;Shen M;Wang L;Chen X;Yuan Y;Dong C;Ma X;Yuan F
角膜新生血管（CoNV）是化学烧伤后视力损害的主要原因。虽然谷氨酰胺代谢在巨噬细胞极化中起着至关重要的作用，但其对参与化学烧伤诱导的角膜损伤的巨噬细胞的调节作用尚不清楚。在这里，我们阐明了巨噬细胞中谷氨酰胺代谢的重编程和碱烧伤诱导的CoNV的发展之间的联系。谷氨酰胺酶1（GLS 1）表达上调，在小鼠角膜损伤与碱烧伤，主要位于F4/80阳性巨噬细胞。选择性口服GLS1抑制剂CB-839（替格列司他）治疗显著降低了碱损伤角膜中极化M2巨噬细胞的分布，并抑制了CoNV的发展。体外研究进一步证明，谷氨酰胺剥夺或CB-839处理抑制来自C57 BL/6J小鼠的骨髓源性巨噬细胞（BMDM）的增殖、粘附和M2极化。CB-839处理显著减弱促血管生成因子的分泌，包括来自白细胞介素-4-（IL-4-）调节的M2巨噬细胞的血管内皮生长因子-A（VEGF-A）和血小板衍生生长因子-BB（PDGF-BB）。我们的研究结果表明，GLS 1抑制或谷氨酰胺剥夺通过抑制巨噬细胞的浸润和M2极化来防止碱诱导的CoNV。这项工作表明，药理学GLS 1抑制是一种可行的和有效的治疗策略，化学烧伤相关的CoNV在人类。
Corneal neovascularization (CoNV) in response to chemical burns is a leading cause of vision impairment. Although glutamine metabolism plays a crucial role in macrophage polarization, its regulatory effect on macrophages involved in chemical burn-induced corneal injury is not known. Here, we elucidated the connection between the reprogramming of glutamine metabolism in macrophages and the development of alkali burn-induced CoNV. Glutaminase 1 (GLS1) expression was upregulated in the mouse corneas damaged with alkali burns and was primarily located in F4/80-positive macrophages. Treatment with a selective oral GLS1 inhibitor, CB-839 (telaglenastat), significantly decreased the distribution of polarized M2 macrophages in the alkali-injured corneas and suppressed the development of CoNV. In vitro studies further demonstrated that glutamine deprivation or CB-839 treatment inhibited the proliferation, adhesion, and M2 polarization of bone marrow-derived macrophages (BMDMs) from C57BL/6J mice. CB-839 treatment markedly attenuated the secretion of proangiogenic factors, including vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) from interleukin-4- (IL-4-) regulated M2 macrophages. Our findings revealed that GLS1 inhibition or glutamine deprivation prevented alkali-induced CoNV by inhibiting the infiltration and M2 polarization of macrophages. This work suggests that pharmacological GLS1 inhibition is a feasible and effective treatment strategy for chemical burn-related CoNV in humans.