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NF-B-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury¹

Medical Biotechnology Center, University of Southern Denmark, Odense, Denmark

Tissue response to injury includes expression of genes encoding cytokines and chemokines. These regulate entry of immune cells to the injured tissue. The synthesis of many cytokines and chemokines involves NF-B and signal transducers and activators of transcription (STAT). Injury to the CNS induces glial response. Astrocytes are the major glial population in the CNS. We examined expression of STATs and the chemokine CCL2 and their relationship to astroglial NF-B signaling in the CNS following axonal transection. Double labeling with Mac-1/CD11b and glial fibrillary acidic protein revealed that STAT2 up-regulation and phosphorylation colocalized exclusively to astrocytes, suggesting the involvement of STAT2 activating signals selectively in astroglial response to injury. STAT1 was also up-regulated and phosphorylated but not exclusively in astrocytes. Both STAT2 up-regulation and phosphorylation were NF-B -dependent since they did not occur in the lesion-reactive hippocampus of transgenic mice with specific inhibition of NF-B activation in astrocytes. We further showed that lack of NF-B signaling significantly reduced injury-induced CCL2 expression as well as leukocyte infiltration. Our results suggest that NF-B signaling in astrocytes controls expression of both STAT2 and CCL2, and thus regulates infiltration of leukocytes into lesion-reactive hippocampus after axonal injury. Taken together, these findings indicate a central role for astrocytes in directing immune-glial interaction in the CNS injury response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants to T.O. from the Danish Agency for Science, Technology and Innovation and from Novo Nordisk Fonden. A.B. was supported by Lundbeckfonden.

² Address correspondence and reprint requests to Dr. Trevor Owens, Medical Biotechnology Center, University of Southern Denmark, Winsloewparken 25, 5000 Odense C, Denmark. E-mail address: towens{at}health.sdu.dk

³ Abbreviations used in this paper: WT, wild type; dpl, days postlesion; GFAP, glial fibrillary acidic protein; PBST, PBS containing 0.5% Triton X-100.

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