Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.
Front Immunol. 2023 Aug 17;14:1187093. doi: 10.3389/fimmu.2023.1187093. eCollection 2023.
Activation of Rho-GTPases in macrophages causes inflammation and severe arthritis in mice. In this study, we explore if Rho-GTPases define the joint destination of pathogenic leukocytes, the mechanism by which they perpetuate rheumatoid arthritis (RA), and how JAK inhibition mitigates these effects.
CD14 cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulators specific for CD14 cells, which were summarized in a metabolic signature (MetSig). The effect of hypoxia and IFN-γ signaling on the metabolic signature of CD14 cells was assessed experimentally. To investigate its connection with joint inflammation, the signature was translated into the single-cell characteristics of synovial tissue macrophages. The sensitivity of MetSig to the RA disease activity and the treatment effect were assessed experimentally and clinically.
CD14 cells carried MetSig of genes functional in the oxidative phosphorylation and proteasome-dependent cell remodeling, which correlated with the cytokine-rich migratory phenotype and antigen-presenting capacity of these cells. Integration of CD14 and synovial macrophages marked with MetSig revealed the important role of the interferon-rich environment and immunoproteasome expression in the homeostasis of these pathogenic macrophages. The CD14 cells were targeted by JAK inhibitors and responded with the downregulation of immunoproteasome and MHC-II molecules, which disintegrated the immunological synapse, reduced cytokine production, and alleviated arthritis.
This study shows that the CDC42-related MetSig identifies the antigen-presenting CD14 cells that migrate to joints to coordinate autoimmunity. The accumulation of CD14 cells discloses patients perceptive to the JAKi treatment.
巨噬细胞中 Rho-GTPases 的激活会导致小鼠炎症和严重关节炎。在这项研究中，我们探讨了 Rho-GTPases 是否定义了致病性白细胞的关节归巢，它们持续引发类风湿关节炎（RA）的机制，以及 JAK 抑制如何减轻这些影响。
通过 RNA 测序和细胞因子测量对 136 名 RA 患者的 CD14 细胞进行了特征分析，以确定 CD14 细胞特有的生物学过程和转录调节剂，并将其总结为代谢特征（MetSig）。实验评估了缺氧和 IFN-γ 信号对 CD14 细胞代谢特征的影响。为了研究其与关节炎症的联系，该特征被转化为滑膜组织巨噬细胞的单细胞特征。实验和临床评估了特征对 RA 疾病活动和治疗效果的敏感性。
CD14 细胞携带与氧化磷酸化和蛋白酶体依赖性细胞重塑相关的基因的 MetSig，这与这些细胞丰富的细胞因子迁移表型和抗原呈递能力相关。整合 CD14 和带有 MetSig 的滑膜巨噬细胞揭示了干扰素丰富的环境和免疫蛋白酶体表达在这些致病性巨噬细胞的稳态中的重要作用。JAK 抑制剂靶向 CD14 细胞，并通过下调免疫蛋白酶体和 MHC-II 分子作出反应，这破坏了免疫突触，减少了细胞因子的产生，并缓解了关节炎。
这项研究表明，CDC42 相关的 MetSig 鉴定了迁移到关节以协调自身免疫的抗原呈递 CD14 细胞。CD14 细胞的积累揭示了对 JAKi 治疗敏感的患者。
