title: p38α (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes.
abstract: In CNS lesions, "reactive astrocytes" form a prominent cellular response. However, the nature of this astrocyte immune activity is not well understood. In order to study astrocytic immune responses to inflammation and injury, we generated mice with conditional deletion of p38α (MAPK14) in GFAP+ astrocytes. We studied the role of p38α signaling in astrocyte immune activation both in vitro and in vivo, and simultaneously examined the effects of astrocyte activation in CNS inflammation. Our results showed that specific subsets of cytokines (TNFα, IL-6) and chemokines (CCL2, CCL4, CXCL1, CXCL2, CXCL10) are critically regulated by p38α signaling in astrocytes. In an in vivo CNS inflammation model of intracerebral injection of LPS, we observed markedly attenuated astrogliosis in conditional GFAPcre p38α(-/-) mice. However, GFAPcre p38α(-/-) mice showed marked upregulation of CCL2, CCL3, CCL4, CXCL2, CXCL10, TNFα, and IL-1β compared to p38αfl/fl cohorts, suggesting that in vivo responses to LPS after GFAPcre p38α deletion are complex and involve interactions between multiple cell types. This finding was supported by a prominent increase in macrophage/microglia and neutrophil recruitment in GFAPcre p38α(-/-) mice compared to p38αfl/fl controls. Together, these studies provide important insights into the critical role of p38α signaling in astrocyte immune activation.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
authors.forename: U
authors.initials: U
authors.lastname: Lo
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Selvaraj
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Plane
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
authors.forename: O V
authors.initials: OV
authors.lastname: Chechneva
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Otsu
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA [2] Medical College, Hubei University of Arts and Science, Xiangyang, Hubei, China [3] Shriners Institute for Pediatric Regenerative Medicine, Sacramento, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology* / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2