Damasceno Luis Eduardo Alves, Cunha Thiago Mattar, Cunha Fernando Queiroz, Sparwasser Tim, Alves-Filho José Carlos
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP 14049-900, Brazil; Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP 14049-900, Brazil; Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany.
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP 14049-900, Brazil; Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP 14049-900, Brazil.
Int Immunopharmacol. 2023 Nov;124(Pt B):111007. doi: 10.1016/j.intimp.2023.111007. Epub 2023 Sep 29.
The STING signaling pathway has gained attention over the last few years due to its ability to incite antimicrobial and antitumoral immunity. Conversely, in mouse models of autoimmunity such as colitis and multiple sclerosis, where T17 cells are implicated in tissue inflammation, STING activation has been associated with the attenuation of immunogenic responses. In this line, STING was found to limit murine T17 pro-inflammatory program in vitro. Here we demonstrate that 2'3'-c-di-AM(PS)(Rp,Rp), a STING agonist that has been undergoing clinical trials for antitumor immunotherapy, activates the STING signalosome in differentiating human T17 cells. Of particular interest, 2'3'-c-di-AM(PS)(Rp,Rp) reduces IL-17A production and IL23R expression by human T17 cells while it favors the generation of regulatory T (T) cells. These findings suggest that STING agonists may be promising approaches for treating human T17-mediated chronic inflammation.
近年来，STING信号通路因其激发抗微生物和抗肿瘤免疫的能力而受到关注。相反，在诸如结肠炎和多发性硬化症等自身免疫性疾病的小鼠模型中，T17细胞参与组织炎症，STING激活与免疫原性反应的减弱有关。在这方面，研究发现STING在体外可限制小鼠T17促炎程序。在此，我们证明2'3'-c-di-AM(PS)(Rp,Rp)，一种正在进行抗肿瘤免疫治疗临床试验的STING激动剂，可在分化的人T17细胞中激活STING信号小体。特别值得注意的是，2'3'-c-di-AM(PS)(Rp,Rp)可减少人T17细胞产生IL-17A和表达IL23R，同时有利于调节性T（Treg）细胞的生成。这些发现表明，STING激动剂可能是治疗人类T17介导的慢性炎症的有前景的方法。
