ABSTRACT
IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6-/- mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6-/- mice showed similar susceptibility to dextran sodium sulfate-induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6-/- mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36γ), but not Il1f8 (IL-36ß), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1ß, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1ß, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling-induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.
Subject(s)
Adjuvants, Immunologic/toxicity , Chemokines/biosynthesis , Colitis/pathology , Imiquimod/toxicity , Interleukin-1/metabolism , Keratinocytes/metabolism , Psoriasis/pathology , Skin/pathology , Th17 Cells/immunology , Animals , Bone Marrow Cells/cytology , Bone Marrow Transplantation , Cells, Cultured , Colitis/chemically induced , Dendritic Cells/metabolism , Dextran Sulfate/toxicity , Fibroblasts/metabolism , Interleukin-1/genetics , Langerhans Cells/metabolism , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Psoriasis/drug therapy , Psoriasis/genetics , Skin/cytology , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/metabolismABSTRACT
The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6(-/-) mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6(-/-) mice and C1qtnf6(-/-) embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H2O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.
