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.

Many annotated long noncoding RNAs (lncRNAs) harbor predicted short open reading frames (sORFs), but the coding capacities of these sORFs and the functions of the resulting micropeptides remain elusive. Here, we report that human lncRNA MIR155HG encodes a 17–amino acid micropeptide, which we termed miPEP155 (P155). MIR155HG is highly expressed by inflamed antigen-presenting cells, leading to the discovery that P155 interacts with the adenosine 5′-triphosphate binding domain of heat shock cognate protein 70 (HSC70), a chaperone required for antigen trafficking and presentation in dendritic cells (DCs). P155 modulates major histocompatibility complex class II–mediated antigen presentation and T cell priming by disrupting the HSC70-HSP90 machinery. Exogenously injected P155 improves two classical mouse models of DC-driven auto inflammation. Collectively, we demonstrate the endogenous existence of a micropeptide encoded by a transcript annotated as “non-protein coding” and characterize a micropeptide as a regulator of antigen presentation and a suppressor of inflammatory diseases.

Peripherally derived regulatory T (pTreg) 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 pTreg-cell generation. miR-31 conditional deletion results in enhanced induction of pTreg 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 pTreg-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 pTreg-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional Treg cells in autoimmune diseases.

The mechanisms underlying tissue-specific chronic inflammation are elusive. Here we report that mice lacking Protein Phosphatase in keratinocytes are predisposed to psoriasis-like skin inflammation, with an inordinate urea cycle and enhanced oxidative phosphorylation that supports hyperproliferation. This phenotype is mediated by increased Arginase-1 production resulting from CCAAT/enhancer-binding protein beta activation. Single-cell RNA-seq of the psoriatic epidermis revealed that the rate-limiting enzyme for Arginine biosynthesis, Argininosuccinate synthetase 1, maintains the Arginine pool, which is indispensable for immune responses.Accumulated polyamines branched from the urea cycle promote endosomal Tlr7-dependent self-RNA sensing by myeloid dendritic cells. This process is achieved with the assistance of an RNA-binding peptide that originates from the heterogeneous nuclear ribonucleoprotein A1, a probable autoantigen in psoriasis. Finally, targeting urea cycle wiring with an arginase inhibitor markedly improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle alteration and excessive polyamine production by psoriatic keratinocytes promote self-RNA sensing by dendritic cells, which links the hyperproliferation of stationary cells with innate-immune activation in an auto-inflammatory condition..