Epidermal Langerhans cells (LCs) are skin-resident dendritic cells that are essential for the induction of skin immunity and tolerance. Transforming growth factor-β 1 (TGFβ1) is a crucial factor for LC maintenance and function. However, the underlying TGFβ1 signaling pathways remain unclear. Our previous research has shown that the TGFβ1/Smad3 signaling pathway does not impact LC homeostasis and maturation. In this study, we generated mice with conditional deletions of either individual Smad2, Smad4, or both Smad2 and Smad4 in the LC lineage or myeloid lineage, to further explore the impact of TGFβ1/Smad signaling pathways on LCs. We found that interruption of Smad2 or Smad4 individually or simultaneously in the LC lineage did not significantly impact the maintenance, maturation, antigen uptake, and migration of LCs in vivo or in vitro during steady state. However, the interruption of both Smad2 and Smad4 pathways in the myeloid lineage led to a dramatic inhibition of bone marrow-derived LCs in the inflammatory state. Overall, our data suggest that canonical TGFβ1/Smad2/4 signaling pathways are dispensable for epidermal LC homeostasis and maturation at steady state, but are critical for the long-term LC repopulation directly originating from the bone marrow in the inflammatory state.
The maintenance of psoriasis as a skin-confined chronic inflammatory condition requires the abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells. In this context, targeting metabolism of keratinocytes is recently reported to be an approach for treating psoriasis, however whether and how the metabolic adaptations of keratinocytes introduce inflammatory cues are unknown. We report that in psoriatic lesions, Protein Phosphatase 6 (PP6) is diminished in the epidermis, and its levels negatively correlate with the disease severity. Mice with genetic deficiency of Pp6 in keratinocytes spontaneously develop psoriasis-like skin phenotype resembling psoriasis clinically, histologically, in its gene expression profile and in its response to therapy. Mechanistically, Pp6-/keratinocytes rely on inordinate urea cycle along with enhanced oxidative phosphorylation (OXPHOS) to hyper-proliferate, mediated by increased Arginase-1 (Arg1) production resulting from the activation of CCAAT/enhancer-binding protein beta (C/EBPb). Single-cell RNA-seq reveals the Arginine biosynthesis rate-limiting enzyme, Argininosuccinate synthetase 1 (ASS1), maintains the pool of Arginine in psoriatic epidermis. Moreover, accumulated polyamines branched from urea cycle promote self-RNA sensing by myeloid dendritic cells with the assistance of an RNA-binding peptide originated from heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), a probable autoantigen in psoriasis, which directly links keratinocyte hyperproliferation to autoimmune responses. Targeting metabolic nodes of urea cycle in imiquimod-induced mouse and non-human primate models of psoriasis markedly improves the skin inflammation. Thus, our data reveal for the first time the molecular basis of an auto-inflammatory condition and the functional significance of target organ-intrinsic metabolic reprogramming in inflammation, bringing forth novel insights into the pathogenesis and therapeutic strategies of chronic inflammatory disorders.
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