Interleukin-33 attenuates sepsis by enhancing neutrophil influx
 to the site of infection

Alves-Filho, J. C. et al. 2010 Nature Medicine 16(6):708-712

Speaker: Wan-Shan Chou (周琬軒)                                    Time: 13:00~14:00, Oct. 27, 2010

Commentator: Dr. Chiou-Feng Lin (林秋烽博士)               Place: Room 601

Abstract:

Sepsis is a serious systemic inflammatory condition caused of microorganism infection with high mortality rate and limited therapeutic strategies (1). Previous studies showed that Toll-like receptors (TLRs) deficiency were associated with an enhanced sepsis survival rate, which suggested that negative regulation of TLRs signalng might be a potential strategy for treating sepsis. IL-33 is a member of IL-1 family, it can bind to the receptor complex consisting of ST2 (IL-1RL1) and IL-1 receptor accessory protein. ST2 was reported not only involved in T_H2 type immune responses, but also negatively regulated TLRs signaling (2). In the present study, the authors found that IL-33 could reduce mortality rate in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33 treatment failed to protect il1rl1 knockout mice from CLP-induced sepsis, which suggested that IL-33 provided a protective effect via IL-33-ST2 signalings. Further results showed that IL-33 treatment could decrease systemic proinflammatory cytokines, chemokines and bacteria load through recruitment of more neutrophils to the infection site in CLP mice. They also found that IL-33 prevented the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLRs in mouse and human neutrophils. TLRs-activated G protein-coupled receptor kinase-2 (GRK2) can induce internalization of chemokine receptors, leading to the CXCR2 downregulation which impairs neutrophilmigration into the infection site during sepsis (3). IL-33 treatment could inhibit TLRs-induced GRK2 upregulation, and prevent the CXCR2 reduction in neutrophils. Furthermore, neutrophils isolated from nonsurvival sepsis patients had less surface CXCR2 expression and chemotaxis than those who survived or healthy. The nonsurvivors also showed significantly higher serum sST2 (soluble ST2, the decoy receptor of IL-33) than those in the survivors, which suggested that IL-33 may play a critical role in clinical sepsis condition. Taken together, the authors found that IL-33 can prevent the TLRs-induced GRK2 induction, maintain the expression of CXCR2, thus empowering neutrophils migration to the infection site for bacterial clearance. This study reveals a previously undescribed mechanism of action of IL-33, and suggests a therapeutic potential of IL-33 in sepsis.

References:

1.      Hotchkiss, R.S. et al. N. Engl. J. Med. 348, 138–150 (2003).

2.      Liew, F.Y. et al. Nat. Rev. Immunol. 10, 103–110 (2010).

3.      Loniewski, K. et al. Mol. Immunol. 45, 2312–2322 (2008).