NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis.

A micropeptide encoded by MIR155HG modulates antigen presentation and suppresses autoinflammation through binding to HSC70.

Peripherally derived regulatory T (pT_reg) cell generation requires T-cell receptor (TCR) signalling and the cytokines TGF-β1 and IL-2. Here we show that TCR signalling induces the microRNA miR-31, which negatively regulates pT_reg-cell generation. miR-31 conditional deletion results in enhanced induction of pT_reg cells, and decreased severity of experimental autoimmune encephalomyelitis (EAE). Unexpectedly, we identify Gprc5a as a direct target of miR-31. Gprc5a is known as retinoic acid-inducible protein 3, and its deficiency leads to impaired pT_reg-cell induction and increased EAE severity. By generating miR-31 and Gprc5a double knockout mice, we show that miR-31 promotes the development of EAE through inhibiting Gprc5a. Thus, our data identify miR-31 and its target Gprc5a as critical regulators for pT_reg-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional T_reg cells in autoimmune diseases.

Retinoic acid inducible‐gene I (RIG‐I) functions as one of the major sensors of RNA viruses. DDX58, which encodes the RIG‐I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG‐I by 5′ppp‐dsRNA, its synthetic ligand, directly causes the production of IL‐23 and triggers psoriasis‐like skin disease in mice. Repeated injections of IL‐23 to the ears failed to induce IL‐23 production and a full psoriasis‐like skin phenotype, in either germ‐free or RIG‐I‐deficient mice. RIG‐I is also critical for a full development of skin inflammation in imiquimod (IMQ)‐induced psoriasis‐like mouse model. Furthermore, RIG‐I‐mediated endogenous IL‐23 production was mainly confined to the CD11c⁺ dendritic cells (DCs) via nuclear factor‐kappa B (NF‐κB) signaling, and stimulated RIG‐I expression in an auto‐regulatory feedback loop. Thus, our data suggest that the dysregulation in the antiviral immune responses of hosts through the innate pattern recognition receptors may trigger the skin inflammatory conditions in the pathophysiology of psoriasis. Synopsis In predisposed individuals, virus infection triggers TLR‐7/8 and/or RIG‐I signaling, subsequently induces IL‐23 in CD11c⁺DCs and mutations in certain genes resulting in impaired regulation of NF‐κB proinflammatory activity, thereby leading to psoriasis. Germ‐free mice fail to develop the IL‐23‐induced psoriasis‐like phenotype. RIG‐I antiviral response triggers IL‐23 production. Development of psoriasis‐like phenotype in mouse models requires RIG‐I. IL‐23 stimulates RIG‐I expression in DCs. RIG‐I‐mediated IL‐23 expression is mainly confined to DCs.