RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

Abstract

Inflammation plays a prominent role in the events following traumatic injury to the central nervous system (CNS). The initial inflammatory response is driven by mediators such as tumor necrosis factor α and interleukin 1β, which are produced by activated astrocytes and microglia at the site of injury. These factors are regulated post-transcriptionally by RNA binding proteins (RBP) that interact with adenylate and uridylate-rich elements (ARE) in the 3'-untranslated region of the messenger RNA (mRNA). Human antigen R (HuR) is one of these RBPs and generally functions as a positive regulator of ARE-containing mRNAs. Here, we hypothesized that HuR plays an important role in the induction of cytokine and chemokines in astrocytes following traumatic injury. Using a mouse model of spinal cord injury, we found HuR to be extensively translocated to the cytoplasm in astrocytes at the level of injury, consistent with its activation. In an in vitro stretch injury model of CNS trauma, we observed a similar cytoplasmic shift of HuR in astrocytes and an attenuation of cytokine induction with HuR knockdown. RNA kinetics and luciferase assays suggested that the effect was more related to transcription than RNA destabilization. A small molecule inhibitor of HuR suppressed cytokine induction of injured astrocytes and reduced chemoattraction for neutrophils and microglia. In summary, HuR is activated in astrocytes in the early stages of CNS trauma and positively regulates the molecular response of key inflammatory mediators in astrocytes. Our findings suggest that HuR may be a therapeutic target in acute CNS trauma for blunting secondary tissue injury triggered by the inflammatory response.

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.…”

“…Genes linked to secondary tissue injury including pro-inflammatory cytokines (e.g., IL-1β and TNF-α) and matrix metalloproteinases (e.g., MMP-9 and 12) increase in the hyperacute phase and are modulated post-transcriptionally [3, 10, 11, 13, 16, 21, 26, 28, 32]. The key elements in post-transcriptional gene regulation are adenine- and uridine-rich elements (AREs) in the 3′ and/or 5′ untranslated regions of mRNA [1, 3, 7].…”

miRNA‑146a attenuates inflammation in an in�vitro spinal cord injury model via inhibition of TLR4 signaling

“…On the one hand, it can eliminate pathogens and necrotic tissue debris, thus establishing the conditions for axon regeneration and tissue remodeling (3). On the other hand, excessive congregation of neurotoxic inflammatory factors and mediators will also aggravate tissue damage (4). Thus, the role of inflammatory response in SCI remains unclear.…”

Mechanisms of autophagy and apoptosis mediated by JAK2 signaling pathway after spinal cord injury of rats

“…Inflammatory response, cell autophagy and cell apoptosis are the important pathogeneses of neuron loss (2–4). Cell autophagy is a major method by which cells can maintain the survival, differentiation and homeostasis.…”