IL-27 controls sepsis-induced impairment of lung antibacterial host defence

Cao, Ju; Xu, Fang; Lin, Shihui; Song, Zigen; Li-pin, Zhang; Luo, Peng; Xu, Huajian; Li, Dairong; Zheng, Ke; Ren, Guosheng; Yin, Yibing

doi:10.1136/thoraxjnl-2014-205777

Cited by 54 publications

(61 citation statements)

References 32 publications

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“…The concentrations of IL-27 are higher in children as compared to adults, further arguing for the usefulness of IL-27 for pediatric cases of sepsis (50). It appears that in human sepsis, plasma levels of heterodimeric IL-27 may be substantially higher as compared to IL-27(p28) detected in our CLP model using time points <24 hours (47). …”

Section: Discussionmentioning

confidence: 63%

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Interruption of Macrophage-Derived IL-27(p28) Production by IL-10 during Sepsis Requires STAT3 but Not SOCS3

Bosmann

Russkamp

Strobl

et al. 2014

The Journal of Immunology

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Severe sepsis and septic shock are leading causes of morbidity and mortality worldwide. Infection-associated inflammation promotes the development and progression of adverse outcomes in sepsis. The effects of heterodimeric Interleukin-27 (IL-27; p28/EBI3) have been implicated in the natural course of sepsis, while the molecular mechanisms underlying regulation of gene expression and release of IL-27 in sepsis are poorly understood. In this report we studied the events regulating the p28 subunit of IL-27 in endotoxic shock and polymicrobial sepsis following cecal ligation and puncture. Neutralizing antibodies to IL-27(p28) improved survival rates, confined cytokine release and reduced bacterial burden in C57BL/6 mice during sepsis. Genetic disruption of IL-27 signaling enhanced the respiratory burst of macrophages. Experiments using splenectomized mice or treatment with clodronate liposomes suggested macrophages in the spleen may be a significant source of IL-27(p28) during sepsis. In cultures of TLR4-activated macrophages, the frequency of F4/80+CD11b+IL-27(p28)+ cells was reduced with addition of IL-10. IL-10 antagonized both MyD88-dependent and TRIF-dependent release of IL-27(p28). Genetic deletion of STAT3 in Tie2-Cre/STAT3flox macrophages completely interrupted the inhibition of IL-27(p28) by IL-10 after TLR4-activation. In contrast, IL-10 remained fully active to suppress IL-27(p28) with deletion of SOCS3 in Tie2-Cre/SOCS3flox macrophages. Blockade of the IL-10 receptor by antibody or genetic deficiency of IL-10 resulted in 3-5-fold higher concentrations of IL-27(p28) in endotoxic shock and polymicrobial sepsis. Our studies identify IL-10 as a critical suppressing factor for IL-27(p28) production during infection-associated inflammation. These findings may be helpful for a beneficial manipulation of adverse IL-27(p28) release during sepsis.

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Section: Discussionmentioning

confidence: 63%

“…1). Treatment with recombinant IL-27 impaired survival following intra-peritoneal challenge with Pseudomonas aeruginosa (47). IL-27RA -/- mice were protected when ‘low-grade’ CLP (=100 % survival) was followed after 24h by intra-tracheal infection with Pseudomonas aeruginosa (47).…”

Section: Discussionmentioning

confidence: 99%

Interruption of Macrophage-Derived IL-27(p28) Production by IL-10 during Sepsis Requires STAT3 but Not SOCS3

Bosmann

Russkamp

Strobl

et al. 2014

The Journal of Immunology

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“…Previous studies have shown that lack of IL-27 signaling increased neutrophil influx to the site of acute bacterial infection in the peritoneal cavity 26 and lung 24 . This raised the question of whether mucosal IL-27 might suppress neutrophil infiltration.…”

Section: Resultsmentioning

confidence: 97%

“…It has been shown that IL-27 influences innate responses to bacterial challenge in the context of systemic sepsis in genetic manipulation models such as IL-27Rα knock-out murine strains. 23,24 . To date, there is no report on the immunosuppressive mechanism of IL27 in acute inflammation of the colon driven by innate cells in a genetically intact, non-infective environment.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses

McLean

Andrews

Hanson

et al. 2017

Inflammatory Bowel Diseases

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Background IBD patients with acute severe colitis face systemic anti-TNF biologic rescue therapy or colectomy, if treatment with intravenous steroids fail. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27 driven mechanisms of immunosuppression in the colonic mucosa. Methods We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, non-infective acute murine colitis model induced by intra-rectal instillation of 2,4,6-Trinitrobenzenesulfonic acid in SJL/J mice. Results IL-27 attenuates acute severe colitis through reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell-independent and IL-10-dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic pro-inflammatory cytokines and induced a multifocal strong positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells. Conclusion We have defined novel mechanisms of IL-27 immunosuppression towards colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for IBD and is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.

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“…IL-27 is critical for the control of sepsis-induced impairment of lung antibacterial host defence. Mice deficient in IL-27 were more resistant to secondary bacterial pneumonia and showed significantly lower bacterial burdens and improved survival, leading to the suggestion that manipulation of the IL-27 pathway has therapeutic potential 11. Neutrophils provide host immunity to Streptococcus pneumonia via a number of pathways.…”

Section: Basic Sciencementioning

confidence: 99%