Induction of Foxp3 and activation of Tregs by HSP gp96 for treatment of autoimmune diseases.
Induction of Foxp3 and activation of Tregs by HSP gp96 for treatment of autoimmune diseases.
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HSP gp96 诱导 Foxp3 并激活 Tregs 治疗自身免疫性疾病
DOI：
10.1016/j.isci.2021.103445
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发表时间：
2021-12-17
期刊：
影响因子：
5.8
通讯作者：
Meng S
中科院分区：
文献类型：
--
作者：
Xu Y;Liu E;Xie X;Wang J;Zheng H;Ju Y;Chen L;Li C;Zhou X;Li Z;Li X;Meng S
调节性T细胞（Tregs）中叉头框蛋白P3（Foxp3）表达的上调与稳定，对于调控Treg功能和免疫稳态至关重要。在本研究中，糖蛋白96（gp96）免疫接种在系统性红斑狼疮的Lyn基因敲除（Lyn–/– ）小鼠模型中显示出明显的治疗效果。此外，gp96减轻了髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎的起始与进展。gp96免疫接种增加了Treg的频率、扩增及抑制功能。基因表达谱分析确定核因子κB（NF-κB）家族成员p65和c-Rel是gp96增强Treg中Foxp3表达的关键转录因子。利用gp96在其Toll样受体（TLR）结合域的突变体、TLR2基因敲除小鼠以及髓样分化因子88（MyD88）细胞特异性敲除小鼠，证实gp96通过TLR2 - MyD88介导的NF-κB信号通路激活Tregs并诱导Foxp3表达。综上所述，这些结果表明，gp96免疫接种通过整合Treg的扩增与激活，限制了抗体诱导和辅助性T细胞（Th）诱导的自身免疫性疾病，这表明其在对抗自身免疫性疾病方面具有潜在的临床应用价值。
- gp96免疫接种可改善Lyn–/–小鼠的系统性红斑狼疮（SLE）症状
- gp96扩增的Tregs在抑制Th介导的实验性自身免疫性脑脊髓炎（EAE）方面具有潜力
- gp96促进Treg的增殖、稳定性及抑制功能
- gp96通过TLR2 - MyD88 - NF-κB - Foxp3通路结合并激活Tregs
免疫反应、基因组学、分子生物学
Upregulation and stabilization of Foxp3 expression in Tregs are essential for regulating Treg function and immune homeostasis. In this study, gp96 immunization showed obvious therapeutic effects in a Lyn–/– mouse model of systemic lupus erythematosus. Moreover, gp96 alleviated the initiation and progression of MOG-induced experimental autoimmune encephalomyelitis. Immunization of gp96 increased Treg frequency, expansion, and suppressive function. Gene expression profiling identified the NF-κB family member p65 and c-Rel as the key transcription factors for enhanced Foxp3 expression in Treg by gp96. Mutant gp96 within its Toll-like receptor (TLR) binding domain, TLR2 knockout mice, and mice with cell-specific deletion of MyD88, were used to demonstrate that gp96 activated Tregs and induced Foxp3 expression via a TLR2-MyD88-mediated NF-κB signaling pathway. Taken together, these results show that gp96 immunization restricted antibody-induced and Th-induced autoimmune diseases by integrating Treg expansion and activation, indicating its potential clinical usefulness against autoimmune diseases. SLE symptoms in Lyn–/– mice are ameliorated by gp96 immunization Tregs expanded by gp96 provide potential in suppressing Th-mediated EAE Gp96 promotes Treg proliferation, stability, and suppressive function Gp96 binds to and activates Treg in a TLR2-MyD88-NF-кB-Foxp3 pathway Immune response, Genomics, Molecular biology
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影响因子：
30.5
作者：
Kitagawa Y;Ohkura N;Kidani Y;Vandenbon A;Hirota K;Kawakami R;Yasuda K;Motooka D;Nakamura S;Kondo M;Taniuchi I;Kohwi-Shigematsu T;Sakaguchi S
通讯作者：
Sakaguchi S
控制FOXP3基因座中的顺式元素对调节T细胞身份的遗传控制。
影响因子：
64.5
作者：
Feng Y;Arvey A;Chinen T;van der Veeken J;Gasteiger G;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
32.4
作者：
Morita H;Arae K;Unno H;Miyauchi K;Toyama S;Nambu A;Oboki K;Ohno T;Motomura K;Matsuda A;Yamaguchi S;Narushima S;Kajiwara N;Iikura M;Suto H;McKenzie AN;Takahashi T;Karasuyama H;Okumura K;Azuma M;Moro K;Akdis CA;Galli SJ;Koyasu S;Kubo M;Sudo K;Saito H;Matsumoto K;Nakae S
通讯作者：
Nakae S
Toll 样受体与分子伴侣 Gp96 的相互作用对于激活细胞毒性 T 淋巴细胞反应至关重要
影响因子：
3.7
作者：
Liu W;Chen M;Li X;Zhao B;Hou J;Zheng H;Qiu L;Li Z;Meng S
通讯作者：
Meng S
DOI：
10.20900/immunometab20200019
发表时间：
2020-01-01
期刊：
Immunometabolism
影响因子：
--
作者：
Hayes, Colleen E;Ntambi, James M
通讯作者：
Ntambi, James M