ABSTRACT
Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.
Subject(s)
Interleukin-17/metabolism , Interleukin-1/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Skin/pathology , T-Lymphocytes/metabolism , Animals , Antibodies/immunology , Antibodies/therapeutic use , Cell Differentiation , Cytokines/metabolism , Disease Models, Animal , Humans , Imiquimod/toxicity , Inflammation/prevention & control , Interleukin-1/genetics , Interleukin-1/pharmacology , Interleukin-1 Receptor Accessory Protein/deficiency , Interleukin-1 Receptor Accessory Protein/genetics , Interleukin-1 Receptor Accessory Protein/metabolism , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Psoriasis/chemically induced , Psoriasis/pathology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Regeneration/drug effects , Skin/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunologySubject(s)
Interleukin-1 Receptor Accessory Protein/genetics , Interleukin-1 Receptor Accessory Protein/metabolism , Animals , Anxiety , Behavior/physiology , Chromosome Pairing/physiology , Disease Models, Animal , Fear/physiology , Humans , Intellectual Disability/genetics , Interleukin-1 Receptor Accessory Protein/deficiency , Interleukin-1 Receptor Accessory Protein/physiology , Memory/physiology , Mice , Mice, Knockout , PhenotypeSubject(s)
Adrenal Hyperplasia, Congenital/genetics , Carbohydrate Metabolism, Inborn Errors/genetics , Chromosome Deletion , Chromosomes, Human, X/genetics , Genes, X-Linked , Genetic Diseases, X-Linked/genetics , Glycerol Kinase/deficiency , Mental Retardation, X-Linked/genetics , Muscular Dystrophy, Duchenne/genetics , Sequence Deletion , Adrenal Cortex Hormones/deficiency , Adrenal Hyperplasia, Congenital/blood , Adrenal Hyperplasia, Congenital/diagnosis , Adrenal Hyperplasia, Congenital/drug therapy , Adrenal Insufficiency , Carbohydrate Metabolism, Inborn Errors/blood , Carbohydrate Metabolism, Inborn Errors/diagnosis , Chromosomes, Human, X/ultrastructure , Creatine Kinase, MM Form/blood , DAX-1 Orphan Nuclear Receptor/deficiency , DAX-1 Orphan Nuclear Receptor/genetics , Dystrophin/deficiency , Dystrophin/genetics , Female , Fludrocortisone/therapeutic use , Genetic Counseling , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/drug therapy , Glycerol Kinase/blood , Glycerol Kinase/genetics , Gonadal Steroid Hormones/deficiency , Heterozygote , Humans , Hydrocortisone/therapeutic use , Hypertriglyceridemia/genetics , Hypoadrenocorticism, Familial , Infant, Newborn , Interleukin-1 Receptor Accessory Protein/deficiency , Interleukin-1 Receptor Accessory Protein/genetics , Male , Mental Retardation, X-Linked/diagnosis , Muscular Dystrophy, Duchenne/blood , Muscular Dystrophy, Duchenne/diagnosis , SyndromeABSTRACT
In the CNS, interleukin-1ß (IL-1ß) is synthesized and released during injury, infection, and disease, mediating inflammatory responses. However, IL-1ß is also present in the brain under physiological conditions, and can influence hippocampal neuronal function. Several cell-specific IL-1-mediated signaling pathways and functions have been identified in neurons and astrocytes, but their mechanisms have not been fully defined. In astrocytes, IL-1ß induced both the p38 MAPK and NF-κB (nuclear factor κB) pathways regulating inflammatory responses, however in hippocampal neurons IL-1ß activated p38 but not NF-κB. Additionally, IL-1ß induced Src phosphorylation at 0.01 ng/ml in hippocampal neurons, a dose 1000-fold lower than that used to stimulate inflammatory responses. IL-1 signaling requires the type 1 IL-1 receptor and the IL-1 receptor accessory protein (IL-1RAcP) as a receptor partner. We previously reported a novel isoform of the IL-1RAcP, IL-1RAcPb, found exclusively in CNS neurons. In this study, we demonstrate that AcPb specifically mediates IL-1ß activation of p-Src and potentiation of NMDA-induced calcium influx in mouse hippocampal neurons in a dose-dependent manner. Mice lacking the AcPb, but retaining the AcP, isoform were deficient in IL-1ß regulation of p-Src in neurons. AcPb also played a modulatory role in the activation of p38 MAPK, but had no effect on NF-κB signaling. The restricted expression of AcPb in CNS neurons, therefore, governs specific neuronal signaling and functional responses to IL-1ß.
Subject(s)
Gene Expression Regulation/drug effects , Interleukin-1 Receptor Accessory Protein/metabolism , Interleukin-1beta/pharmacology , Neurons/drug effects , Protein Isoforms/metabolism , Analysis of Variance , Animals , Astrocytes/drug effects , Astrocytes/physiology , Calcium/metabolism , Cells, Cultured , Dose-Response Relationship, Drug , Embryo, Mammalian , Enzyme Activation/drug effects , Enzyme Activation/genetics , Female , Gene Expression Regulation/physiology , Hippocampus/cytology , Immunoprecipitation , Interleukin-1 Receptor Accessory Protein/deficiency , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , N-Methylaspartate/pharmacology , NF-kappa B/genetics , NF-kappa B/metabolism , Phosphorylation/drug effects , Pregnancy , Protein Isoforms/deficiency , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Time Factors , Transfection , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
IL-33 (IL-1F11) is a recently described member of the IL-1 family of cytokines that stimulates the generation of cells, cytokines, and Igs characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor expressed on Th2 and mast cells. In this study, we demonstrate that IL-33 and ST2 form a complex with IL-1R accessory protein (IL-1RAcP), a signaling receptor subunit that is also a member of the IL-1R complex. Additionally, IL-1RAcP is required for IL-33-induced in vivo effects, and IL-33-mediated signal transduction can be inhibited by dominant-negative IL-1RAcP. The implications of this shared usage of IL-1RAcP by IL-1(alpha and beta) and IL-33 are discussed.
