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

(2015) JOURNAL OF CLINICAL INVESTIGATION. 125(3). p.1329-1338
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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-1 beta 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.
Keywords
INBRED MICE, BALB/C MICE, HOST-DEFENSE, MURINE LEISHMANIASIS, IFN-GAMMA, NITRIC-OXIDE, INTERFERON-GAMMA, T-CELLS, CUTANEOUS LEISHMANIASIS, FACTOR TNF-ALPHA

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Chicago
Gurung, Prajwal, Rajendra Karki, Peter Vogel, Makiko Watanabe, Mark Bix, Mohamed Lamkanfi, and Thirumala-Devi Kanneganti. 2015. “An NLRP3 Inflammasome-triggered Th2-biased Adaptive Immune Response Promotes Leishmaniasis.” Journal of Clinical Investigation 125 (3): 1329–1338.
APA
Gurung, P., Karki, R., Vogel, P., Watanabe, M., Bix, M., Lamkanfi, M., & Kanneganti, T.-D. (2015). An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis. JOURNAL OF CLINICAL INVESTIGATION, 125(3), 1329–1338.
Vancouver
1.
Gurung P, Karki R, Vogel P, Watanabe M, Bix M, Lamkanfi M, et al. An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis. JOURNAL OF CLINICAL INVESTIGATION. 2015;125(3):1329–38.
MLA
Gurung, Prajwal et al. “An NLRP3 Inflammasome-triggered Th2-biased Adaptive Immune Response Promotes Leishmaniasis.” JOURNAL OF CLINICAL INVESTIGATION 125.3 (2015): 1329–1338. Print.
@article{6895893,
  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-1 beta 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.},
  author       = {Gurung, Prajwal and Karki, Rajendra and Vogel, Peter and Watanabe, Makiko and Bix, Mark and Lamkanfi, Mohamed and Kanneganti, Thirumala-Devi},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  keywords     = {INBRED MICE,BALB/C MICE,HOST-DEFENSE,MURINE LEISHMANIASIS,IFN-GAMMA,NITRIC-OXIDE,INTERFERON-GAMMA,T-CELLS,CUTANEOUS LEISHMANIASIS,FACTOR TNF-ALPHA},
  language     = {eng},
  number       = {3},
  pages        = {1329--1338},
  title        = {An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis},
  url          = {http://dx.doi.org/10.1172/JCI79526},
  volume       = {125},
  year         = {2015},
}

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