TLR7 endogenous ligands remodel glycolytic macrophages and trigger skin‐to‐joint crosstalk in psoriatic arthritis. Issue 3 (6th November 2020)

• Record Type: Journal Article
• Authors: Van Raemdonck, Katrien; Umar, Sadiq; Palasiewicz, Karol; Romay, Bianca; Volkov, Suncica; Arami, Shiva; Sweiss, Nadera; Shahrara, Shiva
• Is Part Of: European journal of immunology. Volume 51:Issue 3(2021)
• Page Start: 714
• Page End: 720
• Publication Date: 2020-11-06
• Subjects: Glycolysis -- Macrophages -- miRNA -- Psoriatic arthritis (PsA) -- TLR7; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202048690
• Languages: English
• ISSNs: 0014-2980

Abstract

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. Abstract : TLR7‐activating miRNAs, miR‐29 and miR‐Let7b, were markedly increased in PsA compared to osteoarthritis synovial fluid patient samples. Intradermal (i.d.) miR‐Let7b injection promoted skin inflammation, characterized by Th1 cells and M1 macrophages as well as transcriptional upregulation of glycolytic mediators, GLUT1, C‐MYC and HIF1α. I.d. miR‐Let7b also exacerbated suboptimal joint inflammation, marked similarly by a glycolytic expression profile. In vitro, addition of a TLR7 agonist potentiated metabolic reprogramming of murine macrophages. Moreover, treatment with glycolytic inhibitors, 2‐DG and/or HIF1αi, reversed the TLR7‐driven inflammatory phenotype in M1 macrophages and by extension Th17 cell differentiation. Taken together, this study indicates that TLR7‐instigated metabolic rewiring of macrophages and their cross‐regulation with T cells connects skin immunopathology to joint inflammation.