KSRP: A checkpoint for inflammatory cytokine production in astrocytes

Abstract Chronic inflammation in the central nervous system (CNS) is a central feature of many neurodegenerative and autoimmune diseases. As an immunologically competent cell, the astrocyte plays an important role in CNS inflammation. It is capable of expressing a number of cytokines such as tumor necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β) that promote inflammation directly and through the recruitment of immune cells. Checkpoints are therefore in place to keep tight control over cytokine production. Adenylate/uridylate‐rich elements (ARE) in the 3′ untranslated region of cytokine mRNAs serve as a major checkpoint by regulating mRNA stability and translational efficiency. Here, we examined the impact of KH‐type splicing regulatory protein (KSRP), an RNA binding protein which destabilizes mRNAs via the ARE, on cytokine expression and paracrine phenotypes of primary astrocytes. We identified a network of inflammatory mediators, including TNF‐α and IL‐1β, whose expression increased 2 to 4‐fold at the RNA level in astrocytes isolated from KSRP −/− mice compared to littermate controls. Upon activation, KSRP −/− astrocytes produced TNF‐α and IL‐1β at levels that exceeded control cells by 15‐fold or more. Conditioned media from KSRP −/− astrocytes induced chemotaxis and neuronal cell death in vitro. Surprisingly, we observed a prolongation of half‐life in only a subset of mRNA targets and only after selective astrocyte activation. Luciferase reporter studies indicated that KSRP regulates cytokine gene expression at both transcriptional and post‐transcriptional levels. Our results outline a critical role for KSRP in regulating pro‐inflammatory mediators and have implications for a wide range of CNS inflammatory and autoimmune diseases. © 2012 Wiley Periodicals, Inc.