RESUMO
Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.
Assuntos
RNA Helicases DEAD-box/imunologia , Diarreia Infantil/imunologia , Endorribonucleases/imunologia , Complexo Multienzimático de Ribonucleases do Exossomo , Retardo do Crescimento Fetal/imunologia , Doenças do Cabelo/imunologia , Imunidade Inata/imunologia , Proteínas Nucleares/imunologia , Proteínas Serina-Treonina Quinases/imunologia , RNA Helicases/imunologia , Proteínas de Ligação a RNA/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Proteína DEAD-box 58 , Fácies , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I/imunologia , Camundongos Endogâmicos C57BL , Proteínas/imunologiaRESUMO
Vascular leakage, or edema, is a serious complication of acute allergic reactions. Vascular leakage is triggered by the release of histamine and serotonin from granules within tissue-resident mast cells. Here, we show that expression of Neutrophil Serine Protease 4 (NSP4) during the early stages of mast cell development regulates mast cell-mediated vascular leakage. In myeloid precursors, the granulocyte-macrophage progenitors (GMPs), loss of NSP4 results in the decrease of cellular levels of histamine, serotonin and heparin/heparan sulfate. Mast cells that are derived from NSP4-deficient GMPs have abnormal secretory granule morphology and a sustained reduction in histamine and serotonin levels. Consequently, in passive cutaneous anaphylaxis and acute arthritis models, mast cell-mediated vascular leakage in the skin and joints is substantially reduced in NSP4-deficient mice. Our findings reveal that NSP4 is required for the proper storage of vasoactive amines in mast cell granules, which impacts mast cell-dependent vascular leakage in mouse models of immune complex-mediated diseases.