Regnase-1 D141N mutation induces CD4+ T cell-mediated lung granuloma formation via upregulation of Pim2.

IF 4.8 4区 医学 Q2 IMMUNOLOGY
Thin Sandi Htun, Hiroki Tanaka, Shailendra Kumar Singh, Diego Diez, Shizuo Akira
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Abstract

Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.

Regnase-1 D141N突变通过上调Pim2诱导CD4+ T细胞介导的肺肉芽肿形成。
Regnase-1 是一种 RNase,它通过破坏炎症 mRNA 的稳定性,在负向调节免疫反应方面发挥着关键作用。Regnase-1 的功能障碍可能是导致组织损伤和免疫细胞浸润器官的各种炎症性疾病的主要原因。本研究主要探讨 Regnase-1 的 RNase 活性在炎症性疾病发生中的作用。我们构建了Regnase-1 RNase结构域催化中心单点突变的小鼠,该突变缺乏内切酶活性。D141N突变小鼠表现出全身性炎症、免疫细胞浸润各器官以及肺肉芽肿的进行性发展。主要受该突变影响的 CD4+ T 细胞上调了 mTORC1 通路,促进了 D141N 突变小鼠的自身免疫特征。此外,丝氨酸/苏氨酸激酶Pim2也导致了这种突变的肺部炎症。抑制 Pim2 激酶的活性可改善肺部肉芽肿性炎症、免疫细胞浸润和增殖。此外,抑制 Pim2 还能减少 CD4+ T 细胞上粘附分子的表达,这表明 Pim2 在促进白细胞粘附和向炎症组织迁移方面发挥了作用。我们的研究结果为了解 Regnase-1 RNase 活性在控制免疫功能中的作用提供了新的视角,并强调了靶向 Pim2 以调节异常免疫反应的治疗意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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