Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden.
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530, Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 16, 41346, Gothenburg, Sweden.
J Autoimmun. 2022 Jun;130:102843. doi: 10.1016/j.jaut.2022.102843. Epub 2022 May 25.
Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4 T cells from GLC mice (CD4GLCs). Spleen and joint draining lymph nodes (dLN) CD4GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4GLCs presented a complete signature of GARPNRP1IKZF2FOXP3 regulatory T cells (Tregs) of thymic origin. Activation of the β-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4 cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4 cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthritogenic phenotype.
条件性敲除巨噬细胞中的蛋白异戊烯基转移酶 I（GGTase-I）（GLC）可激活 Rho-GTPases 并导致小鼠发生关节炎。在 GLC 小鼠中敲除 Rag1 可缓解关节炎，这表明淋巴细胞是这些小鼠发生关节炎所必需的。为了研究 GLC 依赖性适应性免疫变化，我们从 GLC 小鼠中分离出 CD4 T 细胞（CD4GLCs）。脾脏和关节引流淋巴结（dLN）中的 CD4GLCs 表现出 Cdc42 和 Rac1 的高表达，这抑制了尾部 HOXA 蛋白并激活了机械感受器复合物以促进迁移。这些富含 CDC42/RAC1 的 CD4GLCs 表现出完全源自胸腺的 GARPNRP1IKZF2FOXP3 调节性 T 细胞（Tregs）的特征。β-catenin/Lef1 轴的激活促进了 Tregs 的促炎 Th1 表型，这与关节炎的严重程度密切相关。在 GLC 小鼠的巨噬细胞中敲除 Cdc42 会影响 CD4 细胞生物学并触发非胸腺 Tregs 的发育。尽管敲除 Rac1 和 RhoA 对 CD4 细胞没有这种作用，但它可以减轻 GLC 小鼠的关节炎。用 CTLA4 融合蛋白破坏巨噬细胞和 T 细胞相互作用可减少 Th1 驱动的炎症和富含胸腺的 Tregs 向 dLN 的募集。抗原刺激会增强非关节炎杂合 GLC 小鼠中的 CD4GLC 表型，并增加表达 Rho-GTPase 的胸腺 Tregs 在 dLN 中的积累。我们的研究表明巨噬细胞在刺激促炎胸腺 Tregs 的发育中具有意想不到的作用，并揭示了 Rho-GTPases 在其致关节炎表型背后的激活作用。
