An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasis
Prajwal Gurung, … , Mohamed Lamkanfi, Thirumala-Devi Kanneganti
Prajwal Gurung, … , Mohamed Lamkanfi, Thirumala-Devi Kanneganti
Published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1329-1338. https://doi.org/10.1172/JCI79526.
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Research Article Immunology

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

Abstract

Leishmaniasis is a major tropical disease that can present with cutaneous, mucocutaneous, or visceral manifestation and affects millions of individuals, causing substantial morbidity and mortality in third-world countries. The development of a Th1-adaptive immune response is associated with resistance to developing Leishmania major (L. major) infection. Inflammasomes are key components of the innate immune system that contribute to host defense against bacterial and viral pathogens; however, their role in regulating adaptive immunity during infection with protozoan parasites is less studied. Here, we demonstrated that the NLRP3 inflammasome balances Th1/Th2 responses during leishmaniasis. Mice lacking the inflammasome components NLRP3, ASC, or caspase 1 on a Leishmania-susceptible BALB/c background exhibited defective IL-1β and IL-18 production at the infection site and were resistant to cutaneous L. major infection. Moreover, we determined that production of IL-18 propagates disease in susceptible BALB/c mice by promoting the Th2 cytokine IL-4, and neutralization of IL-18 in these animals reduced L. major titers and footpad swelling. In conclusion, our results indicate that activation of the NLRP3 inflammasome is detrimental during leishmaniasis and suggest that IL-18 neutralization has potential as a therapeutic strategy to treat leishmaniasis patients.

Authors

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

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Figure 5

NLRP3 inflammasome negatively regulates T cell–mediated IFN-γ production.

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NLRP3 inflammasome negatively regulates T cell–mediated IFN-γ production...
WT (n = 18), Nlrp3–/– (n = 8), Asc–/– (n = 12), and Casp1–/– Casp11–/– (n = 9) mice were infected with 106 L. major promastigotes. Infected mice were euthanized 28 days later, and draining popliteal lymph nodes were harvested. Single-cell suspensions of popliteal lymph node cells were stimulated with anti-CD3 and anti-CD28 antibodies for 4 hours in the presence of monesin. T cells and cytokine production were evaluated by flow cytometry. Representative flow plots of CD4+ (A) and CD8+ T cells (E) that produced IFN-γ. Cumulative bar scatter plots represent the frequencies of CD4+ (B) and CD8+ T cells (F) that produced IFN-γ. Representative flow plot (C) and scatter plot (D) show the mean fluorescence intensity (MFI) of IFN-γ produced by CD4+ T cells. Representative flow plot (G) and scatter plot (H) show the MFI of IFN-γ produced by CD8+ T cells. Dunnett’s multiple comparisons test was used to evaluate significance between groups. Data represent the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.