Immunomodulatory Mechanisms in Hemorrhagic Shock and Sepsis

Hemorrhagic shock and sepsis provoke a complex cascade of innate and adaptive immune responses. Initial insult to the vasculature or infection triggers release of damage-associated molecular patterns (DAMPs) such as cold-inducible RNA-binding protein (CIRP), high-mobility group box 1 and extracellular ATP. These molecules engage pattern recognition receptors on macrophages, endothelial cells and neutrophils, driving cytokine and chemokine production, complement activation and endothelial barrier disruption. Subsequent activation of inflammasomes, notably NLRP3, and cell death pathways including pyroptosis, PANoptosis and NETosis amplify tissue injury. A compensatory anti-inflammatory response follows, marked by lymphocyte apoptosis and reduced antigen presentation, leading to immunosuppression and susceptibility to secondary infection. Therapeutic strategies seek to rebalance this dynamic by neutralising key DAMPs, blocking pro-inflammatory receptors such as TREM-1, modulating inflammasome assembly and harnessing microRNA-based inhibitors. Understanding the temporal interplay between hyperinflammation and immunoparalysis is essential for developing tailored interventions that limit organ damage while preserving host defence.

Research from Nature Portfolio

Studies have delineated how extracellular CIRP directly activates the NLRP3 inflammasome in endothelial cells, inducing caspase-1-dependent pyroptosis and barrier dysfunction in the lung microvasculature. Further work revealed that CIRP engagement of Toll-like receptor 4 in pulmonary endothelium precipitates endoplasmic reticulum stress, upregulating CHOP and caspase-12 and exacerbating acute lung injury. Building on these insights, a peptide derived from CIRP, termed C23, functions as a competitive inhibitor, attenuating systemic inflammation, reducing neutrophil infiltration into the lung and kidney and markedly improving survival in murine sepsis models. These advances underscore the therapeutic potential of targeting DAMP–receptor interactions to modulate immunopathology in shock and sepsis.

Immunomodulatory Mechanisms in Hemorrhagic Shock and Sepsis publication trend

The graph below shows the total number of articles in immunomodulatory mechanisms in hemorrhagic shock and sepsis across all publications each year (not limited to Nature Index journals).

Technical terms

Cold-inducible RNA-binding protein (CIRP): A stress-responsive protein that acts as a DAMP when released extracellularly, promoting inflammation.
DAMPs: Endogenous molecules released by damaged or dying cells that activate innate immune responses.
Inflammasome (NLRP3): A multiprotein complex that detects cellular stress and activates caspase-1 to process pro-inflammatory cytokines and induce pyroptosis.
PANoptosis: A coordinated cell-death programme involving features of pyroptosis, apoptosis and necroptosis.
NETosis: Neutrophil extracellular trap formation, a process by which neutrophils release DNA and granule proteins to trap pathogens.
TREM-1: A receptor on myeloid cells that amplifies inflammation upon binding endogenous or microbial ligands.

References

1. Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. Scientific Reports (2016).
2. Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Scientific Reports (2017).
3. A cold-inducible RNA-binding protein (CIRP)-derived peptide attenuates inflammation and organ injury in septic mice. Scientific Reports (2018).
4. Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway. Military Medical Research (2024).
5. Antigen-presenting aged neutrophils induce CD4+ T cells to exacerbate inflammation in sepsis. Journal of Clinical Investigation (2023).
6. An engineered miRNA PS-OMe miR130 inhibits acute lung injury by targeting eCIRP in sepsis. Molecular Medicine (2023).