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

Abstract

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.

RNA Externalized by Neutrophil Extracellular Traps Promotes Inflammatory Pathways in Endothelial Cells

“…Among the small RNAs contained in the NETs, miR-let-7b was shown to display interferogenic activity on pDCs (37), given its intrinsic ability to act as a natural ligand of TLR-7 (28,31). Recently, miR-let-7b was characterized as an endogenous TLR-7 agonist involved in inflammation propagation in psoriatic arthritis (39). Induction of type I IFN responses in ECs has been linked to the development of vasculopathy and atherothrombosis, particularly in SLE, through pleiotropic effects on vascular repair, inflammation, and coagulation (40)(41)(42)(43).…”

Advances of Genomic Medicine in Psoriatic Arthritis

“…NcRNA-mediated gene silencing constitutes an important type of epigenetic alterations, and ncRNAs are identified as playing important roles in normal physiologic processes, complex human traits, and human diseases [64][65][66]. ncRNAs signatures in PsA have been primarily linked to T cell activation and cytokine signaling, cell proliferation and inflammation, and cartilage/bone metabolism [56,67,68].…”

Synovial Macrophages: Past Life, Current Situation, and Application in Inflammatory Arthritis

“…In addition, it has been shown to exacerbate skin inflammation, suboptimal joint inflammation, and metabolic remodeling of PsA-like preclinical models. Thus, glycolytic inhibitors may act on SMs and reverse skin-joint crosstalk in PsA ( 54 ). Compared with persistent undifferentiated arthritis (UA), the density of CD163 + SMs has been noted to be significantly increased when UA evolves into PsA (UA-PsA).…”