Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis

Abstract

Excessive production of proinflammatory mediators is observed in patients undergoing hemorrhagic and septic shock. Here, we report the detection of cold-inducible RNA-binding protein (CIRP) in the blood of surgical ICU individuals. In animal models of hemorrhage and sepsis, CIRP is up-regulated in several organs and released into the circulation. Under hypoxic stresses, CIRP in macrophages is translocated from the nucleus to the cytosol and actively released. Recombinant CIRP stimulates TNF-α and HMGB1 release in macrophages as well as induces inflammatory responses and causes tissue injury in animals. Antisera to CIRP attenuate shock-induced inflammation, tissue injury, and lethality. Extracellular CIRP's activity is mediated through the TLR4/MD2 complex. Surface plasmon resonance analysis indicates that CIRP binds to the TLR4/MD2 complex as well as to individual TLR4 and MD2. The human CIRP amino-acid segment 106-125 binds to MD2 with high affinity. Collectively, CIRP is a new proinflammatory mediator of shock.

Neuroprotection requires the functions of the RNA-binding protein HuR

“…41 Similarly, Cirbp counteracts cold shock and hypoxia, and also can also enhance stress reactions as in the case of inflammation. 42 Connexin-43 is required for cell polarity, migration and gap-junction formation, but its overexpression enhances gap-junctional communication and arrests developmental programs. 78 The bimodal effects of HuR toward mRNA activation and suppression are suggestive of its involvement in different, tissue-restricted RNP configuration that may include other neuronal RBPs and regulatory RNAs.…”

“…To restrict our analyses to putative HuR targets, we examined whether the human homologs of these 61 mRNAs were identified to physically interact with HuR in PAR-CLiP 36,37 assays deposited in the DoRiNA 38 database; based on phenotypic relevance, we selected six such mRNAs. These included mRNAs encoding for: (a) major energy sensors involved in oxidative metabolism such as Ppargc1a (aka PGC1α), which is a master regulator of ROS-scavenging enzymes, and mitochondrial biogenesis, previously shown to counteract cerebral ischemia; 39 and NQO1 (NAD(P)H dehydrogenase, quinone 1), a major antioxidant whose dysfunction associates with many disease states and cancer; 40 (b) pleiotropic controllers involved in cell survival and cell stress such as Myc 41 and Cirbp (cold-inducible RNA-binding protein); 42 and (c) factors involved in neuronal polarity and plasticity such as semaphorin 3a (Sema3a) and Gja1 (connexin-43). 43 One gene that associated with Elavls but was not identified in DoRiNA (Prkar2a) was also selected because of the relevance of protein kinase A signals to neuronal excitation.…”

The human RBPome: From genes and proteins to human disease

“…In addition to these disorders, RBPs were enriched in various inflammatory diseases such as neuronitis, prostatitis, esophagitis suggesting an important role for RBPs in mediating inflammatory responses. For example, a cold inducible RNA binding protein (CIRBP) that triggers inflammatory responses in hemarragic shock and sepsis was observed to be associated with endothelitis and hypoxia [71]. These results suggest that RBPs are not only implicated in cancers and neurodegenerative diseases but also play an important role in mediating various immunological responses.…”

Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors

“…If dysregulated, the excessive release of these late mediators adversely contributes to the pathogenesis of lethal sepsis (4,(7)(8)(9).…”