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* Department of Nephrology, School of Medicine, Cardiff University, Cardiff, United Kingdom;
Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Victoria, Australia;
Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory, Parkville, Victoria, Australia; and
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom
The successful resolution of inflammation is dependent upon the coordinated transition from the initial recruitment of neutrophils to a more sustained population of mononuclear cells. IL-6, which signals via the common receptor subunit gp130, represents a crucial checkpoint regulator of neutrophil trafficking during the inflammatory response by orchestrating chemokine production and leukocyte apoptosis. However, the relative contribution of specific IL-6-dependent signaling pathways to these processes remains unresolved. To define the receptor-mediated signaling events responsible for IL-6-driven neutrophil trafficking, we used a series of gp130 knockin mutant mice displaying altered IL-6-signaling capacities in an experimental model of acute peritoneal inflammation. Hyperactivation of STAT1 and STAT3 in gp130Y757F/Y757F mice led to a more rapid clearance of neutrophils, and this coincided with a pronounced down-modulation in production of the neutrophil-attracting chemokine CXCL1/KC. By contrast, the proportion of apoptotic neutrophils in the inflammatory infiltrate remained unaffected. In gp130Y757F/Y757F mice lacking IL-6, neutrophil trafficking and CXCL1/KC levels were normal, and this corresponded with a reduction in the level of STAT1/3 activity. Furthermore, monoallelic ablation of Stat3 in gp130Y757F/Y757F mice specifically reduced STAT3 activity and corrected both the rapid clearance of neutrophils and impaired CXCL1/KC production. Conversely, genetic deletion of Stat1 in gp130Y757F/Y757F mice failed to rescue the altered responses observed in gp130Y757F/Y757F mice. Collectively, these data genetically define that IL-6-driven signaling via STAT3, but not STAT1, limits the inflammatory recruitment of neutrophils, and therefore represents a critical event for the termination of the innate immune response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants obtained from The Wellcome Trust (065961 and 069630), the Cardiff Partnership Fund, and the National Health and Medical Research Council of Australia (NHMRC). C.A.F. is a Kidney Research U.K. Career Development Fellow. M.E. was supported by an NHMRC Senior Research Fellowship. B.J.J. was supported by both a R. D. Wright Biomedical Fellowship awarded by the NHMRC and a Monash University Fellowship.
2 C.A.F. and R.M.M. contributed equally to this work.
3 Current address: Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115.
4 Address correspondence and reprint requests to Dr. Brendan J. Jenkins, Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia. E-mail address: Brendan.Jenkins{at}med.monash.edu.au
5 Abbreviations used in this paper: SHP2, Src-homology phosphatase 2; SOCS3, suppressor of cytokine signaling 3; SES, S. epidermidis cell-free supernatant; 7-AAD, 7-aminoactinomycin D.
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