Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection.
Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.
Alves-Filho
Jose C
JC
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
Sônego
Fabiane
F
Souto
Fabricio O
FO
Freitas
Andressa
A
Verri
Waldiceu A
WA
Auxiliadora-Martins
Maria
M
Basile-Filho
Anibal
A
McKenzie
Andrew N
AN
Xu
Damo
D
Cunha
Fernando Q
FQ
Liew
Foo Y
FY
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000276:immunology* / Q000502:physiology; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000276:immunology / Q000502:physiology; D018805:Sepsis / Q000276:immunology* / Q000503:physiopathology; D018417:Th1 Cells / Q000276:immunology / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology / Q000502:physiology; D051193:Toll-Like Receptors / Q000276:immunology / Q000502:physiology
C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D023063:Receptors, Interleukin-8B; D051193:Toll-Like Receptors; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2
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