Jesse Brown VA Medical Center, Chicago, IL, 60612, USA.
Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Cell Mol Immunol. 2021 Sep;18(9):2199-2210. doi: 10.1038/s41423-020-0433-8. Epub 2020 May 15.
Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480iNOS MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480iNOS MΦs, vimentin fibroblasts, and CD3 T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.
类风湿关节炎 (RA) 患者的关节炎症发作和对现有生物治疗药物的耐药性可能反映了固有免疫机制的激活。在此，我们表明，TLR7 GU 富含内源性配体 miR-Let7b 通过放大 RA 单核细胞和成纤维细胞 (FLS) 的迁移来增强滑膜炎。miR-Let7b 与巨噬细胞 (MΦ) 和 FLS 中的 TLR7 结合可扩大滑膜炎症反应。此外，miR-Let7b 触发的 M1 单核因子的分泌增强了 Th1/Th17 细胞的分化。我们表明，IRAK4 抑制剂 (i) 治疗通过阻断 TLR7 诱导的 M1 MΦ 或 FLS 激活以及单核因子调节的 Th1/Th17 细胞极化来减轻 RA 疾病活动。IRAK4i 治疗还破坏了 RA 破骨细胞形成，这是由 miR-Let7b 与关节髓样 TLR7 的结合而放大的。因此，与 TNF 抑制剂 (i) 或抗 IL-6R 治疗在胶原诱导性关节炎 (CIA) 和 miR-Let7b 介导的关节炎中的疗效进行了比较。我们发现，TNF 或 IL-6R 阻断疗法通过减少关节 F480iNOS MΦ 的浸润、某些单核因子的表达和 Th1 细胞分化来减轻 CIA。出乎意料的是，这些生物疗法无法缓解 miR-Let7b 诱导的关节炎。IRAK4i 在 miR-Let7b 诱导的关节炎或 CIA 中的疗效优于抗 TNF 或抗 IL-6R 疗法，这是由于 IRAK4i 疗法能够抑制关节 F480iNOS MΦ、波形蛋白成纤维细胞和 CD3 T 细胞的迁移，此外还否定了广泛的单核因子的表达，包括 IL-12、MIP2 和 IRF5 和 Th1/Th17 淋巴因子。总之，IRAK4i 治疗通过阻断炎症关节细胞之间的关键联系，可能为 RA 治疗提供一种有前途的策略。
