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.

Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

“…RBPs can dramatically affect target mRNA and protein levels. In astrocytes, knockdown of HuR led to a 30–40% attenuation of factors relevant to ischemia such as TNF-α, IL-1β, and MMP-12, whereas knockout of KSRP led to significant increases [13, 20, 21, 24, 26]. These observations provided the basis for our hypothesis that HuR affects secondary tissue injury in experimental ischemic stroke.…”

HuR promotes the molecular signature and phenotype of activated microglia: Implications for amyotrophic lateral sclerosis and other neurodegenerative diseases

“…Multiple components of inflammatory signaling were affected including IL‐6 , IL‐1α , IL‐1β , and Ptgs ( Cox −2), and two amplifiers of cytokine production, Trem‐1 and TremL4 . We previously observed that Trem1 is regulated in astrocytes by KH‐type splicing regulatory protein (KSRP), another ARE‐binding protein which promotes degradation and reduced translation of its target mRNAs (King and Chen, ; Li et al, ). Of the classic factors associated with the M2 phenotype, arginase 1 was significantly attenuated by nearly fourfold (Supporting Information, Table 2).…”

Diverse roles of the nucleic acid‐binding protein KHSRP in cell differentiation and disease

“…Dhamija et al reported that as many as 50 mRNAs that are targets of KHSRP are enriched in polysomes after KHSRP knock‐down and among these mRNAs are those encoding IL6, IL23A, and TNF. Also studies performed in Khsrp −/− astrocytes support a role of KHSRP in TNF and IL1B translation.…”

“…The analysis of KHSRP knockout mice revealed that IFNA and IFNB are upregulated in cells derived from Khsrp −/− mice because of enhanced mRNA half‐life and this regulation explains the robust response of Khsrp −/− mice to viral infections (see Section Role of KHSRP in Viral Infections ). Further, Li et al observed that the expression of TNF and IL1B significantly increased in astrocytes derived from Khsrp −/− mice when compared to wild‐type littermate. Considering that IFNs and cytokines play a crucial role in the pathogenesis of autoimmune diseases, the elucidation of KHSRP function in restraining their expression in immune cells may lead to the development of therapeutic strategies for these pathologies.…”