Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
National Center for Stomatology & National Clinical Research Center of Oral Disease, Shanghai, China.
J Immunol Res. 2022 Feb 15;2022:3210200. doi: 10.1155/2022/3210200. eCollection 2022.
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. , 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 IFN-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFN 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.
先前的研究表明，CD4+T 细胞中异常的代谢重编程可能解释了包括干燥综合征（SS）在内的几种自身免疫性疾病的发生。然而，CD4+T 细胞异常代谢的治疗靶点仍有待探索。在这里，我们报告谷氨酰胺酶 1（Gls1），即谷氨酰胺分解中的关键因素，可能参与 SS 的发病机制。Gls1 的表达在上皮浸润的唇 CD4+T 细胞和 SS 患者的循环 CD4+T 细胞中上调。用 BPTES 抑制 Gls1 可显著抑制 EdU、CFSE 和 Western blot 分析所示的增殖率。此外，BPTES 下调了来自 SS 小鼠的激活的 CD4+T 细胞的细胞外酸化率（ECAR）和耗氧率（OCR）值。为了验证这一机制，我们向 SS 样 NOD/Ltj 小鼠注射了不同剂量的 BPTES，发现 10mg/kg 的 BPTES 可显著恢复唾液流量。组织学和 qRT-PCR 分析表明，这种浓度的 BPTES 可减轻淋巴细胞浸润以及 PCNA 阳性细胞和 CD4+T 细胞的数量。SS 样小鼠唾液腺中 IFN-产生细胞和 IL-17A-产生细胞的比例以及几种促炎细胞因子（包括 IFN 和 IL-17A）的表达也受到影响。对循环血清中的细胞因子进行分析显示，BPTES 下调了 Th17 细胞和 Th1 细胞的效应功能。综上所述，这些结果表明 Gls1 与 SS 发病之间存在正相关关系。用 BPTES 抑制 Gls1 可使 CD4+T 细胞的效应功能正常化，并有效减轻 SS 的症状。
