Interleukin-36α attenuates sepsis by enhancing antibacterial functions of macrophages

Tao, Xintong; Song, Zigen; Wang, Chuanjiang; Luo, Hongchun; Luo, Qin; Lin, Xue; Zhang, Liping; Yin, Yibing; Cao, Ju

doi:10.1093/infdis/jiw535

Cited by 14 publications

(14 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because phagocytes are important for bacterial clearance during sepsis [4, 11, 12], we investigated whether macrophage and/or neutrophil might mediate the beneficial effect of flagellin on sepsis. We first evaluated the importance of macrophages and neutrophils in the survival and bacterial clearance of flagellin-treated septic mice using cell depletion in a sublethal model of sepsis.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Flagellin attenuates experimental sepsis in a macrophage-dependent manner

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis. Methods We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages. Results Therapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)–dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis. Conclusions These novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients. Electronic supplementary material The online version of this article (10.1186/s13054-019-2408-7) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Pathogen-free 6–8-week-old female C57BL/6 mice were obtained from and raised at Chongqing Medical University. Polymicrobial sepsis was provoked by CLP as described in our previous studies [11, 12]. C57BL/6 mice were anesthetized with a mixture of xylazine (4.5 mg/kg) and ketamine (90 mg/kg) intraperitoneally (i.p.).…”

Section: Methodsmentioning

confidence: 99%

Flagellin attenuates experimental sepsis in a macrophage-dependent manner

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pretreatment of macrophages with IL-36a enhances the ability of these cells to phagocytose and destroy Escherichia coli in vitro, which might explain how IL-36a provides protection against the outcome of sepsis induced by cecal ligation and puncture (91). In addition, the presence of IL-1RL2 on B cells (104) and the ability of IL-1RL2 to activate M2 macrophages (95) have been reported; however, the biological importance of these observations has not been examined.…”

Section: Function In Leukocyte Activationmentioning

confidence: 99%

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Jensen

2017

Sci. Signal.

View full text Add to dashboard Cite

Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36a, IL-36b and IL-36g, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1a, IL-1b, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1a, IL-1b, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion.

show abstract

“…Further studies demonstrated that the PKCδ‐TAT peptide inhibitor itself was not cytotoxic and had no bactericidal effects when added directly to cultures of Escherichia Coli or Salmonella Thyphirium in vitro suggesting that PKCδ inhibition may impact immune cell anti‐infective function either directly by impacting phagocyte function or indirectly by altering the environmental milieu. Impaired innate immune cell function has been associated with increased mortality in sepsis …”

Section: Discussionmentioning

confidence: 99%

“…Impaired innate immune cell function has been associated with increased mortality in sepsis. 46 To address this question, we examined immune cell recruitment to the peritoneal cavity and phagocytic capabilities of peritoneal macrophages. As phagocytic cell recruitment to the site of infection is the first line of defense, we examined the impact of PKCδ inhibition on recruitment of neutrophils and monocyte/macrophages.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C‐delta inhibition is organ‐protective, enhances pathogen clearance, and improves survival in sepsis

et al. 2019

View full text Add to dashboard Cite

Sepsis is a leading cause of morbidity and mortality in intensive care units. Previously, we identified Protein Kinase C-delta (PKCδ) as an important regulator of the inflammatory response in sepsis. An important issue in development of anti-inflammatory therapeutics is the risk of immunosuppression and inability to effectively clear pathogens. In this study, we investigated whether PKCδ inhibition prevented organ dysfunction and improved survival without compromising pathogen clearance. SpragueDawley rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Post-surgery, PBS or a PKCδ inhibitor (200µg/kg) was administered intra-tracheally (IT). At 24 hours post-CLP, there was evidence of lung and kidney dysfunction. PKCδ inhibition decreased leukocyte influx in these organs, decreased endothelial permeability, improved gas exchange, and reduced blood urea nitrogen/ creatinine ratios indicating organ protection. PKCδ inhibition significantly decreased bacterial levels in the peritoneal cavity, spleen and blood but did not exhibit direct bactericidal properties. Peritoneal chemokine levels, neutrophil numbers, or macrophage phenotypes were not altered by PKCδ inhibition. Peritoneal macrophages isolated from PKCδ inhibitor-treated septic rats demonstrated increased bacterial phagocytosis. Importantly, PKCδ inhibition increased survival. Thus, PKCδ inhibition improved survival and improved survival was associated with increased phagocytic activity, enhanced pathogen clearance, and decreased organ injury. K E Y W O R D Scecal ligation and puncture, inflammation, macrophages, organ injury, phagocytosis 2498 |

show abstract

Interleukin-36α attenuates sepsis by enhancing antibacterial functions of macrophages

Abstract: Our results demonstrate that IL-36α plays an important role in the host defense response to sepsis and suggest a potential therapeutic role for IL-36α in sepsis.

Cited by 14 publications

References 31 publications

Flagellin attenuates experimental sepsis in a macrophage-dependent manner

Flagellin attenuates experimental sepsis in a macrophage-dependent manner

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Protein kinase C‐delta inhibition is organ‐protective, enhances pathogen clearance, and improves survival in sepsis

Contact Info

Product

Resources

About