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 1

L. major induces inflammasome-mediated IL-1β and IL-18 production by macrophages in vitro.

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L. major induces inflammasome-mediated IL-1β and IL-18 production by ma...
(A and B) BALB/c WT BMDMs were primed with 500 ng/ml LPS for 6 hours followed by the indicated MOI of L. major for 48 hours. Supernatants from stimulated BMDMs were analyzed by ELISA for IL-1β (A) and IL-18 (B). (C and D) WT, Nlrp3–/–, Asc–/–, and Casp1–/– Casp11–/– BMDMs were stimulated with 500 ng/ml LPS for 6 hours followed by L. major infection (20 MOI) for 48 hours, and IL-1β (C) and IL-18 (D) in the supernatants were examined by ELISA. (E) WT and Asc–/– BMDMs were infected with 20 MOI of L. major for 1 hour. Infected BMDMs were washed to get rid of excess L. major and supplemented with fresh media. BMDMs were then immediately stained with Giemsa to determine phagocytosis of L. major (1 hour). Other groups of BMDMs were incubated for an additional 6 and 24 hours to determine clearance of phagocytosed L. major before Giemsa staining of the cells (6-hour and 24-hour time points). Giemsa-stained cells were examined under a light microscope to visualize L. major phagocytosis and clearance (original magnification, ×40). Data in A and B are the mean of duplicates and are representative of at least 3 independent experiments. Data in C and D are cumulative of 3 to 5 independent experiments with n = 3–7 in each group. Images in E are representative of 3 independent experiments. The Mann-Whitney U test was performed to evaluate significant differences between WT and KO BMDMs. ELISA data are shown as the mean ± SEM. *P < 0.05; **P < 0.01.