STAT3 deficiency in B cells exacerbates uveitis by promoting expansion of pathogenic lymphocytes and suppressing regulatory B cells (Bregs) and Tregs.
STAT3 deficiency in B cells exacerbates uveitis by promoting expansion of pathogenic lymphocytes and suppressing regulatory B cells (Bregs) and Tregs.
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DOI：
10.1038/s41598-020-73093-1
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发表时间：
2020-10-01
影响因子：
4.6
通讯作者：
Egwuagu CE
中科院分区：
文献类型：
--
作者：
Oladipupo FO;Yu CR;Olumuyide E;Jittaysothorn Y;Choi JK;Egwuagu CE
STAT 3转录因子诱导幼稚T细胞分化为Th 17细胞，T细胞中STAT 3的缺失防止CNS自身免疫性疾病的发展。然而，STAT 3在B淋巴细胞亚群中的功能还不清楚。在这项研究中，我们已经产生了在CD 19 + B细胞中缺乏STAT 3的小鼠（CD 19-STAT 3 KO），并研究了STAT 3在B细胞中的内在和外在功能及其在器官特异性自身免疫性疾病的抗性或发病机制中的潜在作用。我们表明，STAT 3调节代谢机制，在B细胞的生物能量和代谢途径，控制细胞内稳态在B细胞的影响。因此，CD 19-STAT 3 KO细胞中STAT 3的缺失通过诱导B细胞快速进入细胞周期的S期、降低细胞周期蛋白依赖性激酶抑制剂的表达和上调促凋亡蛋白而扰乱生长和凋亡。我们进一步表明，CD 19-STAT 3 KO小鼠发展严重的实验性自身免疫性葡萄膜炎（EAU），一种人类葡萄膜炎的动物模型。在CD 19-STAT 3 KO小鼠中，葡萄膜炎的加重部分源于B细胞上共刺激分子的表达增强、Th 17应答的显著增加和粒细胞向神经视网膜的募集增加。在B细胞中缺失STAT 3后增强的自身免疫性也在实验性自身免疫性脑炎（多发性硬化的小鼠模型）中重现，因此支持我们的结论，即B细胞中缺失STAT 3增强炎症，并且观察到的作用不是模型特异性的。我们的数据进一步表明，STAT 3途径调节EAU期间B和T细胞之间的相互作用，导致通过增加自身反应性致病性T细胞的水平而改变淋巴细胞库，同时抑制免疫抑制性淋巴细胞（BAF和TAF）的发育和/或扩增。总之，STAT 3在淋巴细胞中发挥完全相反的作用，B细胞中STAT 3的缺失使葡萄膜炎恶化，而T细胞中的STAT 3缺失赋予保护作用。
STAT3 transcription factor induces differentiation of naïve T cells into Th17 cells and loss of STAT3 in T cell prevents development of CNS autoimmune diseases. However, function of STAT3 in the B lymphocyte subset is not well understood. In this study, we have generated mice lacking STAT3 in CD19+ B cells (CD19-STAT3KO) and investigated intrinsic and extrinsic functions of STAT3 in B cells and its potential role in resistance or pathogenesis of organ-specific autoimmune diseases. We show that STAT3 regulates metabolic mechanisms in B cells with implications for bioenergetic and metabolic pathways that control cellular homeostasis in B cells. Thus, loss of STAT3 in CD19-STAT3KO cells perturbed growth and apoptosis by inducing rapid entry of B cells into the S-phase of the cell cycle, decreasing expression of cyclin-dependent kinase inhibitors and upregulating pro-apoptotic proteins. We further show that the CD19-STAT3KO mice develop severe experimental autoimmune uveitis (EAU), an animal model of human uveitis. Exacerbated uveitis in CD19-STAT3KO mice derived in part from enhanced expression of costimulatory molecules on B cells, marked increase of Th17 responses and increased recruitment of granulocytes into the neuroretina. The enhanced autoimmunity upon deletion of STAT3 in B cells is also recapitulated in experimental autoimmune encephalitis, a mouse model of multiple sclerosis and thus support our conclusion that STAT3 deletion in B cells enhanced inflammation and the effects observed are not model specific. Our data further indicate that STAT3 pathway modulates interactions between B and T cells during EAU resulting in alteration of lymphocyte repertoire by increasing levels of autoreactive pathogenic T cells while suppressing development and/or expansion of immune-suppressive lymphocytes (Bregs and Tregs). Taken together, STAT3 exerts diametrically opposite effects in lymphocytes, with loss of STAT3 in B cells exacerbating uveitis whereas Stat3 deletion in T cells confers protection.
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DOI：
10.4049/jimmunol.1502043
发表时间：
2016-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ding C;Chen X;Dascani P;Hu X;Bolli R;Zhang HG;Mcleish KR;Yan J
通讯作者：
Yan J
影响因子：
16.6
作者：
Dambuza IM;He C;Choi JK;Yu CR;Wang R;Mattapallil MJ;Wingfield PT;Caspi RR;Egwuagu CE
通讯作者：
Egwuagu CE
影响因子：
4.4
作者：
Gabriele, Michelle L.;Ishikawa, Hiroshi;Wollstein, Gadi
通讯作者：
Wollstein, Gadi
影响因子：
20.3
作者：
Fornek, JL;Tygrett, LT;Kansas, GS
通讯作者：
Kansas, GS
影响因子：
7.3
作者：
Choi, Jin Kyeong;Dambuza, Ivy M.;Egwuagu, Charles E.
通讯作者：
Egwuagu, Charles E.