Sepsis is characterized by an imbalance in the inflammatory response, immune dysfunction, resulting in life-threatening organ dysfunction, high prevalence, and high mortality. It has been reported that the incidence of sepsis is 1/5 and over a third of patients had died by 90 days in Asia [1]. Globally, sepsis contributes to 11 million deaths annually, representing about approximately 20 % of all causes of death [2].

Immune dysfunction, especially imbalance polarization of CD4+ Th cells, which are the most important peripheral lymphocyte subsets could influence innate and adaptive immune cells, accompany the whole process of the occurrence and development in sepsis [3]. The sepsis-induced immune disorder impact is not only relegated to Th1/Th2 subsets but also to Th17/ regulatory T cell (Treg) subsets as well [4], [5]. Previous clinical studies have reported that increased Th17 differentiation might be associated with survival in patients with severe sepsis [6]. Traumatic shock patients who developed sepsis complication had significantly higher T regulatory cells and lower Th17 cells in comparison to non-sepsis [5]. Another prospective observational study included septic shock patients identified that patients with increased circulating Treg percentage significantly correlated with a decreased lympho-proliferative response, lead to T cell anergy. Furthermore, the proportion of Treg/Th17 was confirmed associated with the severity of patients with sepsis recently [7]. Although the Treg/Th17 imbalance is a vital pathogenesis in sepsis, the precise mechanism under it has not been fully elucidated.

Cold-inducible RNA-binding protein (CIRP) is an ubiquitous intracellular RNA chaperon, which serves as a damage-associated molecular pattern (DAMP) when released outside the cells upon stimulation by inflammation and infection [8]. Accumulating evidence demonstrates that CIRP-mediated systemic inflammation contributes to the pathogenesis of sepsis, and the high concentration of CIRP in circulation is a poor prognostic marker for survival of sepsis [9], [10]. Moreover, it has been shown that CIRP promotes splenic CD4+ and CD8+ T-cell activation in vivo and predisposes CD4+ T cells to a Th1 hyperinflammatory response profile in vitro [11]. However, the effect and underlying mechanisms of CIRP on Treg/Th17 differentiation in sepsis are still unclear.

In the current study, a correlation high circulating CIRP level between Treg/Th17 ratio increasing was observed firstly in clinical. Then, we investigate the role of CIRP in the Treg/Th17 differentiation both in cecal ligation and puncture (CLP) induced-sepsis mice and in vitro. We find that CIRP facilitates Treg expansion during immunosuppressive phase of murine sepsis model. Furthermore, the CIRP promotes Treg cells and inhibits development of Th17 cells by TLR4-IL-2 signaling in vitro. Taken together, our findings show that the CIRP contributes to immune dysfunction through affecting Treg/Th17 homeostasis via TLR4 during sepsis and suggest strategies for therapeutic modulation in Treg/Th17 imbalance inflammatory disease.