IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Ketelut-Carneiro, Natália; Silva, Grace Kelly; Rocha, Fabiana; Milanezi, Cristiane M.; Cavalcanti-Neto, Florêncio Figueiredo; Zamboni, Dario S.; Silva, João

doi:10.4049/jimmunol.1402321

Cited by 83 publications

(85 citation statements)

References 63 publications

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“…Mice and patients infected with P. brasiliensis secrete IL-1β and IL-18, suggesting that NLRP3 is an important player in the recognition of this fungal pathogen (55, 56). The role of NLRP3 using in vivo models of PCM were less explored; however, a recent study using mice systemically infected with P. brasiliensis demonstrated that NLRP3 controls host resistance by inducing a prevalent Th1 immunity associated with IL-18 secretion (40). Because human PCM is acquired by the pulmonary route of infection, in the present study, we sought to characterize the role of NLRP3 inflammasome in i.t.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent work of our lab showed that a dectin-1-Syk mediated mechanism controls NLRP3 inflammasome activation by P. brasiliensis infected macrophages of resistant A/J mice (21). In another study using a murine model of systemic PCM induced by intravenous infection, the susceptibility of NLRP3 and caspase-1 knockout mice to P. brasiliensis infection was evaluated and their increased susceptibility was associated with reduced IL-18 production and Th1 immunity (40). …”

Section: Introductionmentioning

confidence: 99%

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NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

et al. 2017

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The NOD-like receptor P3 (NLRP3) inflammasome is an intracellular multimeric complex that triggers the activation of inflammatory caspases and the maturation of IL-1β and IL-18, important cytokines for the innate immune response against pathogens. The functional NLRP3 inflammasome complex consists of NLRP3, the adaptor protein apoptosis-associated speck-like protein, and caspase-1. Various molecular mechanisms were associated with NLRP3 activation including the presence of extracellular ATP, recognized by the cell surface P2X7 receptor (P2X7R). Several pattern recognition receptors on innate immune cells recognize Paracoccidioides brasiliensis components resulting in diverse responses that influence adaptive immunity and disease outcome. However, the role of NLRP3 inflammasome was scantily investigated in pulmonary paracoccidioidomycosis (PCM), leading us to use an intratracheal (i.t.) model of infection to study the influence of this receptor in anti-fungal immunity and severity of infection. For in vivo studies, C57BL/6 mice deficient for several NLRP3 inflammasome components (Nlrp3−/−, Casp1/11−/−, Asc−/−) as well as deficient for ATP receptor (P2x7r−/−) were infected via i.t. with P. brasiliensis and several parameters of immunity and disease severity analyzed at the acute and chronic periods of infection. Pulmonary PCM was more severe in Nlrp3−/−, Casp1/11−/−, Asc−/−, and P2x7r−/− mice as demonstrated by the increased fungal burdens, mortality rates and tissue pathology developed. The more severe disease developed by NLRP3, ASC, and Caspase-1/11 deficient mice was associated with decreased production of IL-1β and IL-18 and reduced inflammatory reactions mediated by PMN leukocytes and activated CD4+ and CD8+ T cells. The decreased T cell immunity was concomitant with increased expansion of CD4+CD25+Foxp3 regulatory T (Treg) cells. Characterization of intracellular cytokines showed a persistent reduction of CD4+ and CD8+ T cells expressing IFN-γ and IL-17 whereas those producing IL-4 and TGF-β appeared in increased frequencies. Histopathological studies showed that all deficient mouse strains developed more severe lesions containing elevated numbers of budding yeast cells resulting in increased mortality rates. Altogether, these findings led us to conclude that the activation of the NLRP3 inflammasome has a crucial role in the immunoprotection against pulmonary PCM by promoting the expansion of Th1/Th17 immunity and reducing the suppressive control mediated by Treg cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

et al. 2017

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“…Adoptive transfer studies in oral candidiasis have shown that NLRP3 primarily functions in myeloid cells, whereas NLRC4 activity is required in stromal cells. Control of Paracoccidiodes braziliensis in the lungs also requires NLRP3 and caspase-1, although infection is regulated more by IL-18 (also processed by inflammasomes) than by IL-1β (Ketelut-Carneiro et al, 2015). …”

Section: Key Cytokines Involved In Antifungal Immunitymentioning

confidence: 99%

Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street

2015

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We are exposed to a wide spectrum of fungi including innocuous environmental organisms, opportunistic pathogens, commensal organisms, and fungi that can actively and explicitly cause disease. Much less is understood about effective host immunity to fungi than is generally known about immunity to bacterial and viral pathogens. Innate and adaptive arms of the immune system are required for effective host defense against Candida, Aspergillus, Cryptococcus, and others, with specific elements of the host response regulating specific types of fungal infections (e.g., mucocutaneous versus systemic). Here we will review themes and controversies that are currently shaping investigation of antifungal immunity (primarily to Candida and Aspergillus) and will also examine the emerging field of the role of fungi in the gut microbiome.

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“…A recent study has suggested that in addition to LPS, caspase-11 recognizes host-derived oxidized phospholipids, a form of danger-associated molecular pattern that can induce IL-1β release in dendritic cells without triggering pyroptosis (152). Other than A. fumigatus , increased susceptibility of Casp1 −/− Casp11 −/− mice to the fungal pathogens Candida albicans and Paracoccidioides brasiliensis , compared with wild-type mice has also been reported (Table 4) (153–156). In macrophages, pyroptosis induced by C. albicans requires the development of fungal hyphae and/or neutralization of the phagosome (157, 158).…”

Section: Introductionmentioning

confidence: 98%

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

Man

Karki

Kanneganti

2017

Immunological Reviews

1,272

984

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SUMMARY Cell death is a fundamental biological phenomenon that is essential for the survival and development of an organism. Emerging evidence also indicate that cell death contributes to immune defense against infectious diseases. Pyroptosis is a form of inflammatory programed cell death pathway activated by human and mouse caspase-1, human caspase-4 and caspase-5, or mouse caspase-11. These inflammatory caspases are used by the host to control bacterial, viral, fungal or protozoan pathogens. Pyroptosis requires cleavage and activation of the pore-forming effector protein gasdermin D by inflammatory caspases. Physical rupture of the cell causes release of the pro-inflammatory cytokines IL-1β and IL-18, alarmins and endogenous danger-associated molecular patterns, signifying the inflammatory potential of pyroptosis. Here, we describe the central role of inflammatory caspases and pyroptosis in mediating immunity to infection and clearance of pathogens.

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IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Cited by 83 publications

References 63 publications

NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

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