Salman Izadjoo, Kasey E Moritz, Guzal Khayrullina, Elizabeth M Bergman, Brendan M Melvin, Matthew W Stinson, Summer G Paulson, Nikki M McCormack, Kelsey N Anderson, Lunndon A Lewis, Jeremy D Rotty, Barrington G Burnett
{"title":"先天性免疫反应的主要特征是由小胶质细胞中的免疫蛋白酶体介导的。","authors":"Salman Izadjoo, Kasey E Moritz, Guzal Khayrullina, Elizabeth M Bergman, Brendan M Melvin, Matthew W Stinson, Summer G Paulson, Nikki M McCormack, Kelsey N Anderson, Lunndon A Lewis, Jeremy D Rotty, Barrington G Burnett","doi":"10.21203/rs.3.rs-4467983/v1","DOIUrl":null,"url":null,"abstract":"<p><p>Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177974/pdf/","citationCount":"0","resultStr":"{\"title\":\"Key features of the innate immune response is mediated by the immunoproteasome in microglia.\",\"authors\":\"Salman Izadjoo, Kasey E Moritz, Guzal Khayrullina, Elizabeth M Bergman, Brendan M Melvin, Matthew W Stinson, Summer G Paulson, Nikki M McCormack, Kelsey N Anderson, Lunndon A Lewis, Jeremy D Rotty, Barrington G Burnett\",\"doi\":\"10.21203/rs.3.rs-4467983/v1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.</p>\",\"PeriodicalId\":94282,\"journal\":{\"name\":\"Research square\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-06-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177974/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Research square\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.21203/rs.3.rs-4467983/v1\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Research square","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.21203/rs.3.rs-4467983/v1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Key features of the innate immune response is mediated by the immunoproteasome in microglia.
Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.