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

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

doi:10.1172/JCI79526

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

Journal article

Open access

Peer reviewed

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

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

The Journal of clinical investigation, Vol.125(3), pp.1329-1338

03/02/2015

DOI: 10.1172/JCI79526

PMCID: PMC4362229

PMID: 25689249

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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-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.

Details

Title: Subtitle: An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasis
Creators: Prajwal Gurung - Department of Immunology and
Rajendra Karki - Department of Immunology and
Peter Vogel - Department of Animal Resources Center and Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Makiko Watanabe - College of Medicine, Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA
Mark Bix - Department of Immunology and
Mohamed Lamkanfi - Department of Medical Protein Research, Flanders Institute for Biotechnology and
Thirumala-Devi Kanneganti - Department of Immunology and
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.125(3), pp.1329-1338
DOI: 10.1172/JCI79526
PMID: 25689249
PMCID: PMC4362229
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 03/02/2015
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094397702771

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