title: 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.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.forename: Rajendra
authors.initials: R
authors.lastname: Karki
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Makiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Mark
authors.initials: M
authors.lastname: Bix
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D058847:Inflammasomes / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1