ABSTRACT
IL-36R signaling plays an important role in the pathogenesis of psoriasis. We ought to assess the specific function of IL-36R in keratinocytes for the pathology of Aldara-induced psoriasis-like dermatitis. Il36r ΔK mice presenting deletion of IL-36R in keratinocytes were similarly resistant to Aldara-induced ear inflammation as Il36r -/- mice, but acanthosis was only prevented in Il36r -/- mice. FACS analysis revealed that IL-36R signaling in keratinocytes is mandatory for early neutrophil infiltration in Aldara-treated ears. RNASeq and qRT-PCR experiments demonstrated the crucial role of IL-36R signaling in keratinocytes for induction of IL-23, IL-17, and IL-22 at early time points. Taken together, our results demonstrate that IL-36R signaling in keratinocytes plays a major role in the induction of Aldara-induced psoriasis-like dermatitis by triggering early production of IL-23/IL-17/IL-22 cytokines and neutrophil infiltration.
Subject(s)
Drug Eruptions/immunology , Interleukin-23/biosynthesis , Keratinocytes/immunology , Otitis Externa/immunology , Psoriasis/immunology , Receptors, Interleukin-1/deficiency , Signal Transduction/genetics , Administration, Cutaneous , Animals , Drug Eruptions/etiology , Drug Eruptions/metabolism , Female , Gene Deletion , Imiquimod/administration & dosage , Imiquimod/adverse effects , Interleukin-17/biosynthesis , Interleukins/biosynthesis , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Infiltration/drug effects , Neutrophil Infiltration/genetics , Otitis Externa/chemically induced , Psoriasis/chemically induced , Receptors, Interleukin-1/genetics , Signal Transduction/immunology , Interleukin-22ABSTRACT
Antigen cross-presentation by dendritic cells (DC) stimulates cytotoxic T cell activation to promote immunity to intracellular pathogens, viruses and cancer. Phagocytosed antigens generate potent T cell responses, but the signalling and trafficking pathways regulating their cross-presentation are unclear. Here, we show that ablation of the store-operated-Ca2+-entry regulator STIM1 in mouse myeloid cells impairs cross-presentation and DC migration in vivo and in vitro. Stim1 ablation reduces Ca2+ signals, cross-presentation, and chemotaxis in mouse bone-marrow-derived DCs without altering cell differentiation, maturation or phagocytic capacity. Phagosomal pH homoeostasis and ROS production are unaffected by STIM1 deficiency, but phagosomal proteolysis and leucyl aminopeptidase activity, IRAP recruitment, as well as fusion of phagosomes with endosomes and lysosomes are all impaired. These data suggest that STIM1-dependent Ca2+ signalling promotes the delivery of endolysosomal enzymes to phagosomes to enable efficient cross-presentation.
