Adverse functions of IL‐17A in experimental sepsis

Flierl, Michael A.; Rittirsch, Daniel; Gao, Hongwei; Hoesel, Laszlo M.; Nadeau, Brian A.; Day, Danielle E.; Zetoune, Firas S.; Sarma, J. Vidya; Huber‐Lang, Markus; Ferrara, James L.M.; Ward, Peter A.

doi:10.1096/fj.07-105221

Cited by 181 publications

(213 citation statements)

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“…IL-17 plays an important pathogenic role in sepsis [9]. To demonstrate the role of IL-17-expressing gd T cells in the development of sepsis, here both mild grade sepsis and high grade sepsis models were used.…”

Section: Il-17 Was Secreted Mainly By CD T Cells In Clp-induced Sepsismentioning

confidence: 99%

“…IL-17 (also known as IL-17A) is a proinflammatory cytokine produced by a variety of cells including CD4 1 Th17 cells, CD8 1 T cells, neutrophils and NK cells [8]. Recent reports also suggested that gd T cells are a major source of IL-17 [9]. Although it has been demonstrated that IL-17 plays an important role in defense against extracellular pathogens such as Klebsiella pneumoniae [10], production and regulation of IL-17, interaction of IL-17 with other critical pro-inflammatory cytokine in sepsis, remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Cell cytometry showed that IL-17 was predominantly expressed in gd T cells (Fig. 2B), indicating that gd T cells were a major source for IL-17 in CLP mice.IL-17 plays an important pathogenic role in sepsis [9]. To demonstrate the role of IL-17-expressing gd T cells in the development of sepsis, here both mild grade sepsis and high grade sepsis models were used.…”

mentioning

confidence: 99%

“…However, evidence of the impact of IL-17 on sepsis pathogenesis was quite contradictory. IL-17 may not only mediate CpG-inducible host defense during intra-abdominal sepsis [18], but may also play adverse functions in experimental sepsis [9]. Additionally, its prevalence and the mechanisms by which IL-17 is generated and regulated in sepsis are unclear.…”

mentioning

confidence: 99%

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Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Xu¹,

Wang²,

Han³

et al. 2010

Eur J Immunol

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Complement 5a (C5a) and are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by cd T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by cd T cells. Dendritic cells (DC) were found to act as a ''bridge'' between C5a and cd T cells in a mechanism involving IL-6 and transforming growth factor b (TGF-b). These results imply that C5a affects the crosstalk between DC and cd T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17.Key words: Complement system . gd T cells . Immunopathology IntroductionSepsis is a life-threatening medical condition caused by various microorganisms entering the human bloodstream and triggering an uncontrolled inflammatory reaction. In light of the multifactorial pathogenesis of sepsis, extensive work has been done to characterize the numerous agents and mediators that are involved in sepsis. In spite of extensive research efforts over the last 20 years, sepsis remains the leading cause of death in intensive care units [1,2]. Specific therapies are generally unavailable because pathogenic mechanisms are still unclear.There is abundant evidence that complement activation, production of cytokines and other inflammatory responses occur in sepsis [3]. It is generally accepted that the complement activation product complement 5a (C5a) plays an important inflammatory role in rodents following cecal ligation and puncture (CLP) [4]. C5a exerts its effects through the high-affinity C5a receptor (C5aR) and C5L2. C5L2, a putative ''default'' receptor, has been suggested to play important role in balancing the biological effect of C5a. For example, recent data showed that both C5aR and C5l2 cooperatively play functional parts in the setting of sepsis [5]. It has been shown that blockade of C5a or its receptor (C5aR) can inhibit the development of CLP and is associated with decreased levels of bacteria, preservation of innate immune functions of blood neutrophils, reduced thymocyte apoptosis and greatly improved survival rates [6,7].IL-17 (also known as IL-17A) is a proinflammatory cytokine produced by a variety of cells including CD4 1 Th17 cells, CD8 1 T cells, neutrophils and NK cells [8]. Recent reports also suggested that gd T cells are a major source of . Although it has been demonstrated that IL-17 plays an important role in Ã These authors contributed equally to this paper. Understanding crosstalk between critical pathogenic factors may be very important for designing treatments for sepsis. Here, we studied the crosstalk between two critical pathogenic factors, C5a and IL-17. Our results show that C5a acted on DC, which subsequently induced gd T cells to secrete IL-17. ResultsC5a induced IL-17 in CLP-induce...

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Section: Il-17 Was Secreted Mainly By CD T Cells In Clp-induced Sepsismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Xu¹,

Wang²,

Han³

et al. 2010

Eur J Immunol

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“…On the other hand, other authors demonstrated that the blockage of IL-17A was protective in cecal ligation and puncture (CLP)-induced sepsis. These authors associated the protective effects of IL-17A blockade with a reduction in the levels of bacteremia and of systemic proinflammatory cytokines and chemokines (41).…”

Section: Il-17 Receptor Signaling Is Required To Controlmentioning

confidence: 99%

IL-17 Receptor Signaling Is Required to Control Polymicrobial Sepsis

Freitas

Alves‐Filho

Victoni

et al. 2009

The Journal of Immunology

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Sepsis is a systemic inflammatory response resulting from the inability of the host to contain the infection locally. Previously, we demonstrated that during severe sepsis there is a marked failure of neutrophil migration to the infection site, which contributes to dissemination of infection, resulting in high mortality. IL-17 plays an important role in neutrophil recruitment. Herein, we investigated the role of IL-17R signaling in polymicrobial sepsis induced by cecal ligation and puncture (CLP). It was observed that IL-17R-deficient mice, subjected to CLP-induced non-severe sepsis, show reduced neutrophil recruitment into the peritoneal cavity, spread of infection, and increased systemic inflammatory response as compared with C57BL/6 littermates. As a consequence, the mice showed an increased mortality rate. The ability of IL-17 to induce neutrophil migration was demonstrated in vivo and in vitro. Beside its role in neutrophil recruitment to the infection focus, IL-17 enhanced the microbicidal activity of the migrating neutrophils by a mechanism dependent on NO. Therefore, IL-17 plays a critical role in host protection during polymicrobial sepsis.

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IL‐17A/p38 Signaling Pathway Induces Alveolar Epithelial Cell Pyroptosis and Hyperpermeability in Sepsis‐Induced Acute Lung Injury by Activating NLRP3 Inflammasome

Zhou,

He,

Liu

et al. 2023

Advanced Biology

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Sepsis is a syndrome with poor prognosis. Nucleotide‐binding domain‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome and T helper 17 (Th17) cells are involved in the pathogenesis of inflammatory diseases. This study aims to explore their roles and underlying mechanisms in sepsis. The blood and bronchoalveolar lavage fluid are collected from sepsis patients and healthy donors. A sepsis mice model is established by cecal ligation puncture (CLP). The contents of cytokines are detected by ELISA. The amounts of Th17 cells, IL‐17A, IL‐1β, IL‐18, and lipopolysaccharide is significantly elevated in sepsis patients. The increased differentiation of Th17 cells can promote lung cell pyroptosis and induce hyperpermeability via activating NLRP3 inflammasome and p38 pathway. The inhibitors targeting Th17 cells, NLRP3 inflammasome, and p38 pathway can significantly alleviate lung injury in sepsis mice. Th17 cells can secrete IL‐17A to activate NLRP3 inflammasome via p38 signaling pathway, which contributes to the development of sepsis‐induced acute lung injury.

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Adverse functions of IL‐17A in experimental sepsis

Cited by 181 publications

References 45 publications

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

IL-17 Receptor Signaling Is Required to Control Polymicrobial Sepsis

IL‐17A/p38 Signaling Pathway Induces Alveolar Epithelial Cell Pyroptosis and Hyperpermeability in Sepsis‐Induced Acute Lung Injury by Activating NLRP3 Inflammasome

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