IL-33 protects mice from sepsis by inhibiting TLR4 signaling
© BioMed Central Ltd 2009
Published: 11 November 2009
Sepsis is an acute systemic inflammation following infection, with a high mortality rate and limited therapeutic options. IL-33 is a recently identified member of the IL-1 family that binds to ST2 receptor, which is preferentially expressed on Th2 and mast cells. Accordingly, the IL-33/ST2 pathway is closely associated with the activation and production of type-II cytokines (IL-4, IL-5 and IL-13). However, ST2 has been implicated in inhibiting macrophage-dependent inflammation in response to LPS by negatively regulating Toll-like receptor-4 (TLR4) activation. Although TLRs have been implicated as an important element of host defense against infections, evidence indicates that these receptors may also play a detrimental role in the pathophysiology of sepsis.
To investigate the role of the IL-33/ST2 pathway in experimental sepsis.
Methods and results
We show that IL-33 treatment (1 μg/mouse, intravenously) markedly reduced mortality in WT mice (50%, P < 0.01) undergoing experimental sepsis induced by the cecal ligation and puncture (CLP) model. We did not detect any differences between ST2 KO and WT mice in peritoneal bacterial load and mortality rate after CLP, suggesting that the endogenous IL-33 does not participate in the pathophysiology sepsis. However, while the exogenous injection of IL-33 markedly reduced the CLP-induced mortality in WT mice, IL-33 failed to do so in ST2-/- mice, indicating the critical role of ST2 on the protective effect of IL-33. Notably, we found that IL-33-treated mice developed significantly increased neutrophil infiltration in the peritoneal cavity (fourfold) and more efficient bacterial clearance than untreated mice (n = 10) after CLP. Moreover, IL-33 treatment leads to marked reduction (30 to 70%) of systemic proinflammatory cytokines (TNFα, IL-6 and CXCL2) but not a shift toward a Th2 immune response (IL-4 and IL-13). The chemokine receptor CXCR2 plays a central role in the recruitment of neutrophils into the site of infection. Flow cytometry analysis showed that direct activation of TLR4 in neutrophils downregulates the expression of CXCR2 and, consequently, impaired CXCL2-driven and CLP-driven neutrophil migration, in vitro and in vivo respectively. Notably, IL-33 prevented the downregulation of CXCR2 on circulating neutrophils during CLP in vivo or LPS-treated neutrophils in vitro. Finally, we demonstrated that IL-33 reversed the TLR4-induced reduction of CXCR2 via the inhibition of LPS-induced G-protein-coupled receptor kinase-2 (GRK2) expression, a potent negative regulator of CXCR2.
Altogether we provide here a novel mechanism of action of IL-33 and establish a potential therapeutic role of this new cytokine in sepsis.
Financial support from Wellcome Trust, MRC and FAPESP.