p38α (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes

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 p38 alpha (MAPK14) in GFAP+ astrocytes. We studied the role of p38 alpha 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 (TNF alpha, IL-6) and chemokines (CCL2, CCL4, CXCL1, CXCL2, CXCL10) are critically regulated by p38 alpha signaling in astrocytes. In an in vivo CNS inflammation model of intracerebral injection of LPS, we observed markedly attenuated astrogliosis in conditional GFAPcre p38 alpha(-/-) mice. However, GFAPcre p38 alpha(-/-) mice showed marked upregulation of CCL2, CCL3, CCL4, CXCL2, CXCL10, TNF alpha, and IL-1 beta compared to p38 alpha fl/fl cohorts, suggesting that in vivo responses to LPS after GFAPcre p38 alpha 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 p38 alpha(-/-) mice compared to p38 alpha fl/fl controls. Together, these studies provide important insights into the critical role of p38 alpha signaling in astrocyte immune activation.