Neutrophils Produce Interleukin 17A (IL-17A) in a Dectin-1- and IL-23-Dependent Manner during Invasive Fungal Infection

Werner, Jessica L.; Gessner, Melissa; Lilly, Lauren M.; Nelson, Michael Paul; Metz, Allison E.; Horn, Dawn; Dunaway, Chad W.; Deshane, Jessy; Chaplin, David; Weaver, Casey T.; Brown, Gordon D.; Steele, Chad

doi:10.1128/iai.05493-11

Cited by 156 publications

(160 citation statements)

References 45 publications

(47 reference statements)

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“…93 Similarly, in an experimental model of pulmonary A. fumigatus colonization in immunocompetent mice, clearance of the fungus from the airways was associated with the development of Th17 responses, 145 and IL-17 production by neutrophils has been found to be protective in a model of A. fumigatus keratitis. 144 Similar conflicting results have been reported from human studies. A. fumigatus was a weak inducer of IL-17 production in human T-cells in vitro, and low levels of IL-17 were detected in the bronchoalveolar lavage (BAL) of patients with IA.…”

Section: The Adaptive Immune Response To Aspergillosis In Hsct Patientscontrasting

confidence: 47%

“…3,143 An initial study reported that neutralization of IL-17 and IL-23 in immunocompetent mice improved the outcome of IA and suggested that the IL-23/IL-17 axis inhibits protective Th1 mediated responses while inducing damaging host inflammatory responses. 144 However, other studies using anti-IL-17 antibodies have reported that neutralization of IL-17A renders mice more susceptible to A. fumigatus infection. 93 Similarly, in an experimental model of pulmonary A. fumigatus colonization in immunocompetent mice, clearance of the fungus from the airways was associated with the development of Th17 responses, 145 and IL-17 production by neutrophils has been found to be protective in a model of A. fumigatus keratitis.…”

Section: The Adaptive Immune Response To Aspergillosis In Hsct Patientsmentioning

confidence: 98%

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Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

Al-Bader

Sheppard

2016

Virulence

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Invasive aspergillosis is a life-threatening infection caused by the opportunistic filamentous fungus Aspergillus fumigatus. Patients undergoing haematopoietic stem cell transplant (HSCT) for the treatment of hematological malignancy are at particularly high risk of developing this fatal infection. The susceptibility of HSCT patients to infection with A. fumigatus is a consequence of a complex interplay of both fungal and host factors. Here we review our understanding of the hostpathogen interactions underlying the susceptibility of the immunocompromised host to infection with A. fumigatus with a focus on the experimental validation of fungal and host factors relevant to HSCT patients. These include fungal factors such as secondary metabolites, cell wall constituents, and metabolic adaptations that facilitate immune evasion and survival within the host microenvironment, as well as the innate and adaptive immune responses involved in host defense against A. fumigatus.

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Section: The Adaptive Immune Response To Aspergillosis In Hsct Patientscontrasting

confidence: 47%

Section: The Adaptive Immune Response To Aspergillosis In Hsct Patientsmentioning

confidence: 98%

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

Al-Bader

Sheppard

2016

Virulence

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“…Depleting either CD4 + T cells or neutrophils singly in gal3 +/+ mice significantly reduced the IL-17A level (Fig. 4C), indicating that resembling infection by Aspergillus fumigatus, neutrophils, in addition to CD4 + T cells, contribute to IL-17A production in histoplasmosis (44). Interestingly, depleting neutrophils singly completely abolished IL-17A production.…”

Section: Discussionmentioning

confidence: 87%

“…4E). Comparing neutrophils purified from A. fumigatus-infected dectin-1 2/2 mice with cells from infected dectin-1 +/+ mice, Werner et al (44) reported that, although Rorc (Rorgt) mRNA is significantly higher in the former than in the latter, IL-17A production is incoordinately lower in the former. It appears that, unlike in Th17 cells, IL-17A expression in neutrophils in response to IL-23 stimulation is not under the transcription regulation of RORgt.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 Negatively Regulates Dendritic Cell Production of IL-23/IL-17–Axis Cytokines in Infection by Histoplasma capsulatum

Liu

et al. 2013

The Journal of Immunology

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Galectin-3 (gal3) is known for its immunoregulatory functions in infectious, autoimmune, and inflammatory diseases. However, little is known about its regulatory role in the host's IL-17A response to infection. Using a mouse model of histoplasmosis in which both Th1 and Th17 responses contribute to fungal clearance, we investigated how gal3 regulates IL-17A responses. Our study showed that Histoplasma infection induced gal3−/− dendritic cells to produce significantly higher levels of IL-23, TGF-β1, and IL-1β than did gal3+/+ cells. Infected by the same inoculum of Histoplasma, gal3−/− mice had lower fungal burden and produced higher levels of IL-23/IL-17–axis cytokines and lower levels of IL-12 and IFN-γ. Additionally, there was an increase in Th17 cells and a reduction in Th1 cells in infected gal3−/− mice. In vitro Th1/Th17-skewing experiments excluded the intrinsic effect of gal3 on Th cell differentiation. Although neutrophils from both gal3+/+ and gal3−/− mice produced IL-17A upon IL-23 stimulation, their contribution to IL-17A production was greater in gal3−/− mice than in gal3+/+ mice. Compared with gal3+/+ dendritic cells, adoptive transfer of gal3−/− dendritic cells resulted in production of significantly higher levels of IL-17–axis cytokines and reduced fungal burden. It appears that reduced fungal burden and preferential IL-17A response in gal3−/− mice by both Th17 cells and neutrophils were the result of preferential production of IL-23/IL-17–axis cytokines by dendritic cells. Our study showed that gal3 negatively regulates IL-17A responses through inhibition of IL-23/IL-17–axis cytokine production by dendritic cells.

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“…The production of both is influenced by dectin-1. In candidiasis, the mechanisms by which dectin-1 regulates IL-17A/IL-17F production and in which innate immune cells this occurs is not known, but it is of interest that both neutrophils 37 and c-dT cells 38 produce IL-17A via dectin-1. Altogether, our data indicate that the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background and affects both the innate production of IL-17A, IL-17F and IL-22 and the regulation of the Th1/Th17/Treg balance in adaptive immunity.…”

mentioning

confidence: 99%

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

et al. 2012

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The recognition of b-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor-dependent IL-22 production and in adaptive Th1 responses. In contrast, the resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/ noncanonical NF-kB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling.

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Neutrophils Produce Interleukin 17A (IL-17A) in a Dectin-1- and IL-23-Dependent Manner during Invasive Fungal Infection

Cited by 156 publications

References 45 publications

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

Galectin-3 Negatively Regulates Dendritic Cell Production of IL-23/IL-17–Axis Cytokines in Infection by Histoplasma capsulatum

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

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