An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasis

Gurung, Prajwal; Karki, Rajendra; Vogel, Peter; Watanabe, Makiko; Bix, Mark; Lamkanfi, Mohamed; Kanneganti, Thirumala‐Devi

doi:10.1172/jci79526

Cited by 125 publications

(147 citation statements)

References 47 publications

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“…A role for NLRP3 has also observed in leishmania infection in mice, in which NLRP3-dependant production of IL-18 propagates disease in susceptible BALB/c mice by promoting the T H 2 cytokine IL-4 (ref. 35).…”

Section: Discussionmentioning

confidence: 99%

The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

et al. 2015

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The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.

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Section: Discussionmentioning

confidence: 99%

The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

et al. 2015

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“…Although IL-1b is known to initiate a Th1 response, IL-18-mediated control over Th1/Th2 skewing is dependent on the local cytokine milieu. Indeed, IL-18 was shown to contribute to detrimental Th2 responses in both infectious disease (60) and sterile inflammatory contexts (61), and it was suggested as a useful biomarker to assess AD severity in humans (62,63); all of these data support the notion that IL-18 may also contribute to skin disease in cpdm mice.…”

Section: Discussionmentioning

confidence: 81%

The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice

Douglas

Champagne

Morizot

et al. 2015

The Journal of Immunology

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Chronic proliferative dermatitis in mice (cpdm) is a spontaneous multiorgan inflammatory disorder with pathological hallmarks similar to atopic dermatitis and psoriasis in humans. Cpdm mice lack expression of SHANK-associated RH domain–interacting protein, an adaptor of the linear ubiquitin assembly complex, which acts in the NF-κB pathway to promote inflammation and protect from apoptosis and necroptosis. Although skin inflammation in cpdm mice is driven by TNF- and RIPK1-induced cell death, the contribution of initiating innate immunity sensors and additional inflammatory pathways remains poorly characterized. In this article, we show that inflammasome signaling, including the expression and activation of the inflammatory caspase-1 and -11 and IL-1 family cytokines, was highly upregulated in the skin of cpdm mice prior to overt disease onset. Genetic ablation of caspase-1 and -11 from cpdm mice significantly reduced skin inflammation and delayed disease onset, whereas systemic immunological disease persisted. Loss of Nlrp3 also attenuated skin disease, albeit more variably. Strikingly, induction of apoptosis and necroptosis effectors was sharply decreased in the absence of caspase-1 and -11. These results position the inflammasome as an important initiating signal in skin disease pathogenesis and provide novel insights about inflammasome and cell death effector cross-talk in the context of inflammatory diseases.

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“…Following killing, popliteal lymph nodes and spleen were harvested. Single cell suspension of cells from lymph node and spleen were made as described previously (35). Cells were then stained for neutrophils Model showing IL-1β-mediated inflammation and bone disease in Pstpip2 cmo mice.…”

Section: Methodsmentioning

confidence: 99%

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Gurung

Burton

Kanneganti

2016

Proc. Natl. Acad. Sci. U.S.A.

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112

115

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Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production in Pstpip2cmo mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease in Pstpip2cmo mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 in Pstpip2cmo mice provides similar protection as observed in caspase-1 and caspase-8–deficient Pstpip2cmo mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease in Pstpip2cmo mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseased Ptpn6spin neutrophils. Data from our chimera studies demonstrated that IL-1β produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1β signaling is unidirectional and feedback signaling of IL-1β onto the hematopoietic compartment is not important for disease induction. In conclusion, our studies have uncovered the combined actions of the NLRP3 inflammasome and caspase 8 leading to IL-1β maturation and the directionality of IL-1β in driving disease in Pstpip2cmo mice.

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An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasis

Cited by 125 publications

References 47 publications

The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

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