Thirty percent of psoriasis patients develop psoriatic arthritis (PsA), nevertheless the mechanism remains unknown. Endogenous GU‐rich miRNAs activate endosomal TLR7 that plays a critical role in autoimmune diseases. We found that endogenous TLR7 ligands, miR‐29 and miR‐Let7b, were markedly increased in PsA compared to osteoarthritis (OA) synovial fluid (SF)s. We showed that intradermal (i.d.) miR‐Let7b injection promoted skin inflammation, which was characterized by amplified Th1 cells, CD68⁺M1 macrophages, and transcriptional upregulation of glycolytic mediators, GLUT1, C‐MYC, and HIF1α. Expansion of skin Th1 cells driven by miR‐Let7b was also linked to elevated M1‐associated IRFs. Interestingly, i.d. miR‐Let7b administration exacerbated suboptimal joint inflammation along with metabolic reconfiguration of the PsA‐like preclinical model. Moreover, TLR7 agonist, R837, potentiated metabolic reprogramming and expression of IL‐1β, IL‐6, and IL‐12 in murine macrophages, enabling myeloid‐to‐T‐cell crosstalk. Consistently, treatment with glycolytic inhibitors, 2‐DG and/or HIF1αi, reversed R837‐induced metabolic remodeling and disrupted the TLR7‐driven inflammatory phenotype in myeloid and lymphoid cells. Similar to miR‐Let7b, R837 also differentiates progenitor cells into mature osteoclasts, primarily through RANKL induction. Taken together, this study indicates that TLR7‐instigated metabolic rewiring of macrophages and their cross‐regulation of T cells connects skin immunopathology to joint inflammation.

中文翻译：

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TLR7 内源性配体重塑糖酵解巨噬细胞并引发银屑病关节炎中的皮肤与关节串扰

30% 的银屑病患者会发展为银屑病关节炎 (PsA)，但其机制仍然未知。内源性富含 GU 的 miRNA 可激活在自身免疫性疾病中起关键作用的内体 TLR7。我们发现，与骨关节炎 (OA) 滑液 (SF) 相比，内源性 TLR7 配体 miR-29 和 miR-Let7b 在 PsA 中显着增加。我们发现皮内 (id) miR-Let7b 注射促进了皮肤炎症，其特征是 Th1 细胞扩增，CD68 ⁺M1 巨噬细胞和糖酵解介质、GLUT1、C-MYC 和 HIF1α 的转录上调。由 miR-Let7b 驱动的皮肤 Th1 细胞的扩增也与 M1 相关 IRF 升高有关。有趣的是，id miR-Let7b 给药加剧了不理想的关节炎症以及 PsA 样临床前模型的代谢重构。此外，TLR7 激动剂 R837 可增强小鼠巨噬细胞中 IL-1β、IL-6 和 IL-12 的代谢重编程和表达，从而实现髓系与 T 细胞的串扰。一致地，用糖酵解抑制剂 2-DG 和/或 HIF1αi 治疗可逆转 R837 诱导的代谢重塑并破坏骨髓和淋巴细胞中 TLR7 驱动的炎症表型。与 miR-Let7b 类似，R837 也主要通过 RANKL 诱导将祖细胞分化为成熟的破骨细胞。综合起来，