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

Lo U, Selvaraj V, Plane JM, Chechneva OV, Otsu K, Deng W - Sci Rep (2014)

Bottom Line: 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.Together, these studies provide important insights into the critical role of p38α signaling in astrocyte immune activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.

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.

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Immunostaining and quantification of chemokine and cytokine protein expression in the brain of GFAPCre p38α−/− and p38αfl/fl mice after intracerebral LPS injection.(A) The immunoreactivity of CCL2, CXCL10 and IL-6 was observed in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation. (B) Quantification of immunoreactive cells expressing CCL2, CXCL10 and IL-6 and the expression of CCL2, CXCL10 and IL-6 in the population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation.
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f7: Immunostaining and quantification of chemokine and cytokine protein expression in the brain of GFAPCre p38α−/− and p38αfl/fl mice after intracerebral LPS injection.(A) The immunoreactivity of CCL2, CXCL10 and IL-6 was observed in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation. (B) Quantification of immunoreactive cells expressing CCL2, CXCL10 and IL-6 and the expression of CCL2, CXCL10 and IL-6 in the population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation.

Mentions: To corroborate these results based on mRNA levels using an alternative approach by immunohistochemical analysis of cytokine and chemokine expression, we performed and verified the immunoreactivity of CCL2, CXCL10 and IL-6 in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS challenge (Fig. 7A). Quantification of immunoreactive cells expressing CCL2, CXCL10 and IL-6 showed the increased expression of CCL2, CXCL10 and IL-6 and particularly their expression in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice after LPS stimulation (Fig. 7B).


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

Lo U, Selvaraj V, Plane JM, Chechneva OV, Otsu K, Deng W - Sci Rep (2014)

Immunostaining and quantification of chemokine and cytokine protein expression in the brain of GFAPCre p38α−/− and p38αfl/fl mice after intracerebral LPS injection.(A) The immunoreactivity of CCL2, CXCL10 and IL-6 was observed in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation. (B) Quantification of immunoreactive cells expressing CCL2, CXCL10 and IL-6 and the expression of CCL2, CXCL10 and IL-6 in the population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264013&req=5

f7: Immunostaining and quantification of chemokine and cytokine protein expression in the brain of GFAPCre p38α−/− and p38αfl/fl mice after intracerebral LPS injection.(A) The immunoreactivity of CCL2, CXCL10 and IL-6 was observed in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation. (B) Quantification of immunoreactive cells expressing CCL2, CXCL10 and IL-6 and the expression of CCL2, CXCL10 and IL-6 in the population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS stimulation.
Mentions: To corroborate these results based on mRNA levels using an alternative approach by immunohistochemical analysis of cytokine and chemokine expression, we performed and verified the immunoreactivity of CCL2, CXCL10 and IL-6 in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice at 6 hours after LPS challenge (Fig. 7A). Quantification of immunoreactive cells expressing CCL2, CXCL10 and IL-6 showed the increased expression of CCL2, CXCL10 and IL-6 and particularly their expression in the increased population of CD68+ cells in the brain of GFAPcre p38α−/− mice compared to p38αfl/fl mice after LPS stimulation (Fig. 7B).

Bottom Line: 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.Together, these studies provide important insights into the critical role of p38α signaling in astrocyte immune activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.

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.

Show MeSH
Related in: MedlinePlus