Extracellular Cold-Inducible RNA-Binding Protein: Progress from Discovery to Present

Abstract

Extracellular cold-inducible RNA-binding protein (eCIRP) is a critical damage-associated molecular pattern (DAMP) that drives inflammation and tissue injury in hemorrhagic and septic shock, and has emerged as a promising therapeutic target. Since then, extensive research using preclinical models of diseases and patient materials has explored eCIRP's role in driving inflammatory responses and its potential as a biomarker. The main objective of this comprehensive review is to provide a detailed overview of eCIRP, covering its discovery, role in disease pathophysiology, mechanisms of release and action, potential as a biomarker, and therapeutic strategies targeting eCIRP in preclinical models of inflammatory and ischemic diseases. We examine the molecular, cellular, and immunological mechanisms through which eCIRP contributes to disease progression, and explore both well-established and emerging areas of research. Furthermore, we discuss potential therapeutic strategies targeting eCIRP across a broad spectrum of inflammatory conditions, including shock, ischemia-reperfusion injury, neurodegenerative diseases, and radiation injury.

Keywords: DAMPs; diseases; immune cells; immunity; inflammation.

Figure 1

Three-dimensional configuration of CIRP. The human cold-inducible RNA-binding protein (CIRP; Q14011) amino acid sequence was retrieved from the UniProt database (https://www.uniprot.org/uniprotkb/Q14011/entry, accessed on 25 March 2025), and its protein structure was modeled using the I-TASSER tool (https://zhanggroup.org/I-TASSER/, accessed on 25 March 2025). I-TASSER generates structural models based on templates, using a threading approach to maximize percentage identity, sequence coverage, and confidence score. The resulting model was further refined, improving parameters such as the percentage of Ramachandran-favored residues and reducing the number of poor rotamers. Human CIRP contains an RNA-binding domain (RBD) (residues 6–84) and arginine–glycine–glycine (RGG)-rich domains (residues 94–96, 105–107, and 116–118). The RGG-rich domains are required for translational repression. The refined three-dimensional structural model was visualized using PyMOL v3.0.

Figure 2

Role of extracellular CIRP in acute and chronic inflammatory diseases. eCIRP was discovered in 2013 as a critical DAMP that exacerbates inflammation and organ injury in sepsis and hemorrhagic shock via TLR4. From 2013 to 2020, considerable progress was made in elucidating its pathophysiology in a wide range of inflammatory diseases, including the discovery of a new receptor, TREM-1, and a new therapeutic compound targeting eCIRP/TREM-1 interactions. This period also depicts the discovery of eCIRP’s role beyond macrophages, in other cells such as neutrophils, T cells, and endothelial cells. Further progress in the eCIRP field occurred between 2020 and 2025, with the elucidation of another eCIRP receptor, IL-6R, which plays a pivotal role in immune tolerance. Additional discoveries included eCIRP’s role in macrophage phagocytic dysfunction, the polarization of B-1a cells from an immunoregulatory to a pro-inflammatory phenotype by targeting Siglec-G, the induction of endothelial cell PANoptosis by increasing ZBP1 expression, and the promotion of neurodegeneration by enhancing Ca²⁺ influx and CDK5 expression in neuronal cells, a novel pathophysiology in Alzheimer’s disease. eCIRP, extracellular CIRP; DAMP, damage-associated molecular pattern; TLR4, Toll-like receptor 4; TREM-1, triggering receptor expressed on myeloid cells-1; PANoptosis, pyroptosis, apoptosis, necroptosis; ZBP1, Z-DNA-binding protein 1; Siglec-G, sialic acid binding Ig-like lectin-G; CDK5, cyclin-dependent kinase 5.