IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance

Zelante, Teresa; Luca, Antonella De; Bonifazi, Pierluigi; Montagnoli, Claudia; Bozza, Silvia; Moretti, Silvia; Belladonna, Maria Laura; Vacca, Carmine; Conte, Carmela; Mosci, Paolo; Bistoni, Francesco; Puccetti, Paolo; Kastelein, Robert A.; Köpf, Manfred; Romani, Luigina

doi:10.1002/eji.200737409

Cited by 506 publications

(537 citation statements)

References 41 publications

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“…Our findings corroborate those of others showing that IL-17 potentiates in vitro neutrophil killing of pneumococcus (55). However, they are in apparent contradiction with the demonstration that IL-17 reduces neutrophil antifungal activity (56). The use of different neutrophil microbial targets may explain the observed differences.…”

Section: Discussionsupporting

confidence: 77%

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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Section: Discussionsupporting

confidence: 77%

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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“…28 We found that the rs11209026 variant in donor was associated with decreased risk of fungal infections and, IL-23/Th17 genetic variants in transplantation A Carvalho et al in patient, with improved OS, a finding consistent with the protective effects of IL-23 signaling attenuation in experimental aspergillosis. 25 The fact that donor rs11209026 also increased the risk of CMV infection, while consistent with the enhancing role of IL-23 of antiviral immunity, 39 indicates that fungal more than CMV infection may impact on OS in our cohort of patients. Although the variant could arguably influence OS by modifying the incidence of disease relapse or GVHD, a beneficial effect on relapse was only demonstrated in the univariate analysis and no effect on GVHD was found whatsoever.…”

Section: Discussionsupporting

confidence: 68%

“…19 It appears that an imbalance between Th17 and regulatory T cells (Treg) ultimately associates with the development of transplant rejection. 20,21 Considering that the role of Th17 cells in protection vs pathology in infectious diseases is also controversial, with protective 11,22,23 and detrimental 12,24,25 effects being reported, it follows that genetic variants affecting the expression of cytokines of the IL-23/Th17 pathway may have a role in transplantation outcome.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation

Carvalho

Cunha

Ianni

et al. 2010

Bone Marrow Transplant

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T helper (Th) 17 cells have emerged as important mediators in infectious and inflammatory diseases and, recently, in transplant rejection. We analyzed the associations between five common genetic variants in the IL-23/ Th17 signaling pathway, namely in IL17A, IL17F and IL23R genes, and clinical outcome in T cell-depleted allogeneic SCT (allo-SCT). In the multivariate analysis, variants in IL23R and IL17A genes were the most important prognostic factors. Thus, patient GA genotype at rs11209026 in IL23R was associated with improved overall survival (hazard ratio (HR) ¼ 0.48; P ¼ 0.028) and, in donor, with decreased risk of fungal infections (P ¼ 0.05). In contrast, patient TC and CC genotypes at rs8193036 in IL17A gene were associated with increased risk of CMV infection (HR ¼ 3.68; P ¼ 0.011) and patient acute GVHD (HR ¼ 7.08; P ¼ 0.008), respectively. These results suggest that genetic variants in the IL-23/Th17 inflammatory pathway are important prognostic factors for the clinical outcome of allo-SCT. Although validation studies are ultimately required, our results would suggest the potential usefulness of IL-23/Th17 genotyping in donor selection and patient evaluation.

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“…However, there is also evidence that IL-23 and IL-17 may have a negative role in immunity to fungal infection. IL-23p19 À/À mice were less susceptible to intragastric infection with C. albicans and intranasal infection with Aspergillus fumigatus and this was associated with enhanced IL-12 and IFN-g production [94]. This study concluded that IL-23 and IL-17 impaired the anti-fungal immunity by suppressing Th1 responses and the fungicidal activity of neutrophils.…”

Section: Role Of Il-17-secreting T Cells In Infectionmentioning

confidence: 72%

“…IFN-g may also play a role in controlling pathogenic T cells in autoimmunity by inducing peripheral conversion of CD4 1 CD25 À T cells into CD4 1 FoxP3 1 Treg cells [102]. While all these reports suggest that IFN-g may suppress induction of Th17 cells, there is also evidence that IL-23 and IL-17 may negatively regulate IFN-g production; anti-IL-23 and anti-IL-17 enhanced IFN-g production in mice with fungal infections [94]. It has also been demonstrated that IFN-g can enhance IL-23p19 and IL-12p40 mRNA, whereas IL-4 suppresses IL-12p19 and IL-12p40 in response to Sendai virus infection [103].…”

Section: Regulation Of Il-17-secreting T Cellsmentioning

confidence: 99%

Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance

Cited by 506 publications

References 41 publications

IL-17 Receptor Signaling Is Required to Control Polymicrobial Sepsis

IL-17 Receptor Signaling Is Required to Control Polymicrobial Sepsis

Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation

Induction, function and regulation of IL‐17‐producing T cells

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