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 6

IL-18 promotes Th2 responses during T cell activation in BALB/c mice.

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IL-18 promotes Th2 responses during T cell activation in BALB/c mice. Si...
Single-cell suspensions of splenocytes from WT BALB/c mice were stimulated for 72 hours with anti-CD3 Ab in the presence of IL-1β and IL-18. IFN-γ (A) and IL-4 (B) cytokine levels in the supernatants were determined by ELISA. (C) WT BALB/c splenocytes were stimulated for 72 hours with anti-CD3 in the presence of IL-18 and IL-18BP, and IL-4 levels in the supernatants were determined by ELISA. (D–F) WT BALB/c mice were treated with PBS (n = 10) or IL-18BP (n = 10) on days –1, 0, 1, 3, 7, and 14. Mice were infected with 106 L. major promastigotes, and footpad swelling was monitored on days 14 and 21 (D and E). (F) IL-4 cytokine levels in the footpads of infected mice were determined on day 21 after infection. (G and H) Single-cell suspensions of splenocytes from WT BALB/c mice were stimulated for 48 hours with anti-CD3 Ab in the presence of IL-1β and IL-18, and expression of GATA3 was determined by flow cytometry. (G) Representative histogram plots of GATA3 expression. (H) MFI of GATA3 in CD4+ T cells. Data in A–C are presented as duplicates from 3 to 4 WT mice and are representative of at least 5 independent experiments. Data in G and H are presented as duplicates from 2 WT mice and are representative of 2 independent experiments. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 by Mann-Whitney U test.