TLR7 endogenous ligands remodel glycolytic macrophages and trigger skin-to-joint crosstalk in psoriatic arthritis

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 HIF1 alpha. 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-1 beta, IL-6, and IL-12 in murine macrophages, enabling myeloid-to-T-cell crosstalk. Consistently, treatment with glycolytic inhibitors, 2-DG and/or HIF1 alpha i, 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.

Automated summary

This study reveals that miR-Let7b activates TLR7 and induces skin inflammation, exacerbating joint inflammation in a PsA-like preclinical model. TLR7 agonist R837 promotes metabolic reprogramming in macrophages and enhances the expression of IL-1 beta, IL-6, and IL-12, facilitating myeloid-to-T-cell crosstalk in mice. Inhibiting glycolysis reverses TLR7-driven inflammation in myeloid and lymphoid cells, suggesting a potential therapeutic target for PsA.