Cold-inducible RNA-binding protein activates splenic T cells during sepsis in a TLR4-dependent manner

Abstract

Cold-inducible RNA-binding protein (CIRP) is a novel inflammatory mediator that stimulates the release of proinflammatory cytokines from macrophages in sepsis. Given the immune dysregulation that characterizes sepsis, the effect of CIRP on other immune cells is an area of increasing interest that has not yet been studied. In the present study, we hypothesized that extracellular CIRP promotes activation of T lymphocytes in the spleen during sepsis. We observed that mice subjected to sepsis by cecal ligation and puncture showed significantly higher expression of the early activation markers CD69 and CD25 at 20 h on CD4 splenic T cells, and significantly higher CD69 expression on CD8 splenic T cells compared with sham-operated controls. Furthermore, at 20 h after receiving intravenous injection of recombinant murine CIRP (rmCIRP, 5 mg/kg body weight (BW)) or PBS (vehicle), those mice receiving rmCIRP showed significantly increased expression of CD69 and CD25 on both CD4 and CD8 splenic T cells. This effect, however, was not seen in TLR4-deficient mice after rmCIRP injection. In addition, treatment with CIRP predisposed CD4 T cells to a Th1 hyperinflammatory response profile, and influenced CD8 T cells toward a cytotoxic profile. Taken together, our findings indicate that CIRP is a proinflammatory mediator that plays an important role in T-cell dysregulation during sepsis in a TLR4-dependent manner.

Extracellular CIRP (eCIRP) and inflammation

“…). Mice injected recombinant CIRP showed significantly increased the expression of activation markers on CD4 + and CD8 + splenic T cells . This effect, however, was not seen in TLR4‐deficient mice .…”

“…eCIRP‐induced lung injury is characterized by increased infiltration of neutrophils into the lungs, increased vascular endothelial permeability, and activation of vascular endothelial cells . The effects of eCIRP and its mechanism of action have already been studied in a number of immune cells, including macrophages, lymphocytes, neutrophils, and dendritic cells . eCIRP's effects have also been studied in endothelial and epithelial cells (Fig.…”

“…During sepsis, T cells are activated, as evidenced by increased expression of CD69 and CD25 in CD4 + splenic T cells and of CD69 in CD8 + splenic T cells . Excessive T‐cell activation, however, leads to T‐cell exhaustion via activation‐induced cell death (AICD) .…”

“…eCIRP then acts as a DAMP increasing macrophage production of proinflammatory cytokines . Since its original discovery as a DAMP, eCIRP's emerging proinflammatory role has been progressively extended to include additional target cells, such as neutrophils, lymphocytes, epithelial cells, and endothelial cells . eCIRP promotes inflammation by binding to the TLR4‐MD2 receptor complex, leading to the activation and nuclear translocation of the transcription factor NF‐κB .…”

Extracellular CIRP as a Novel Endogenous TREM-1 Ligand to Fuel Inflammation

“…Similar to other DAMPs, eCIRP recognizes Toll-like receptor 4 (TLR4) 5,8 expressed in macrophages, lymphocytes, and neutrophils to increase cytokine production 5 , T cell polarization 9 , and neutrophil activation 10 . Healthy mice injected with recombinant murine (rm) CIRP developed acute lung injury (ALI) via activation of macrophages, neutrophils, and endothelial cells, and displayed increased vascular permeability in the lungs 11,12 .…”