Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren's Syndrome.
Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren's Syndrome.
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DOI：
10.1155/2022/3210200
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发表时间：
2022
影响因子：
4.1
通讯作者：
Zheng L
中科院分区：
文献类型：
--
作者：
Fu J;Pu Y;Wang B;Li H;Yang X;Xie L;Shi H;Wang Z;Yin J;Zhan T;Shao Y;Chen C;Luo Q;Xu J;Zong Z;Wei X;Xiao W;Yu C;Zheng L
先前的研究表明，CD4+ T 细胞中异常的代谢重编程可以解释包括干燥综合征 (SS) 在内的多种自身免疫性疾病的发生。然而，CD4+ T细胞代谢异常的治疗靶点仍有待探索。在此，我们报道谷氨酰胺酶 1 (Gls1) 作为谷氨酰胺分解的关键因子，可能参与 SS 的发病机制。 SS 患者浸润的唇部 CD4+ T 细胞和循环 CD4+ T 细胞中 Gls1 的表达上调。 EdU、CFSE 和蛋白质印迹分析表明，用 BPTES 抑制 Gls1 可显着降低增殖率。此外，BPTES 下调了 SS 小鼠活化 CD4+ T 细胞的细胞外酸化率 (ECAR) 和耗氧率 (OCR) 值。在体内，我们向SS样NOD/Ltj小鼠注射不同剂量的BPTES，发现10mg/kg BPTES显着恢复唾液流速。组织学和 qRT-PCR 分析表明，该浓度的 BPTES 减弱了淋巴细胞浸润以及 PCNA 阳性细胞和 CD4+ T 细胞的数量。 SS样小鼠唾液腺中产生IFNγ的细胞和产生IL-17A的细胞的比例以及包括IFNγ和IL-17A在内的几种促炎细胞因子的表达也受到影响。对循环血清中细胞因子产生的分析表明，BPTES 下调了 Th17 细胞和 Th1 细胞的效应功能。总的来说，这些结果表明 Gls1 和 SS 发育之间存在正相关关系。用 BPTES 对 Gls1 进行药理抑制可以使 CD4+ T 细胞的效应功能正常化，并有效减轻 SS 的症状。
Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren's syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.