The NLRP3 Inflammasome Suppresses Protective Immunity to Gastrointestinal Helminth Infection

Rafid Alhallaf; Zainab Agha; Catherine M Miller; Avril A B Robertson; Javier Sotillo; John Croese; Matthew A Cooper; Seth L Masters; Andreas Kupz; Nicholas C Smith; Alex Loukas; Paul R Giacomin

doi:10.1016/j.celrep.2018.03.097

The NLRP3 Inflammasome Suppresses Protective Immunity to Gastrointestinal Helminth Infection

Cell Rep. 2018 Apr 24;23(4):1085-1098. doi: 10.1016/j.celrep.2018.03.097.

Authors

Affiliations

¹ Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, QLD 4878, Australia.
² College of Public Health, Medical and Veterinary Sciences, James Cook University, Smithfield, QLD 4878, Australia.
³ School of Chemistry and Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
⁴ Department of Gastroenterology and Hepatology, The Prince Charles Hospital, Brisbane, QLD 4032, Australia.
⁵ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
⁶ Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁷ Research School of Biology, Australian National University, Canberra, ACT 0200, Australia; School of Science and Health, Western Sydney University, Parramatta South Campus, NSW 2116, Australia.
⁸ Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, QLD 4878, Australia. Electronic address: paul.giacomin@jcu.edu.au.

PMID: 29694887
DOI: 10.1016/j.celrep.2018.03.097

Abstract

Inflammasomes promote immunity to microbial pathogens by regulating the function of IL-1-family cytokines such as IL-18 and IL-1β. However, the roles for inflammasomes during parasitic helminth infections remain unclear. We demonstrate that mice and humans infected with gastrointestinal nematodes display increased IL-18 secretion, which in Trichuris-infected or worm antigen-treated mice and in macrophages co-cultured with Trichuris antigens or exosome-like vesicles was dependent on the NLRP3 inflammasome. NLRP3-deficient mice displayed reduced pro-inflammatory type 1 cytokine responses and augmented protective type 2 immunity, which was reversed by IL-18 administration. NLRP3-dependent suppression of immunity partially required CD4⁺ cells but was apparent even in Rag1^-/- mice that lack adaptive immune cells, suggesting that NLRP3 influences both innate and adaptive immunity. These data highlight a role for NLRP3 in limiting protective immunity to helminths, suggesting that targeting the NLRP3 inflammasome may be an approach for limiting the disease burden associated with helminth infections.

Keywords: IL-18; NLRP3; exosomes; goblet cells; helminth; immunopathology; inflammasome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity*
Animals
Antigens, Helminth / immunology*
Cytokines / genetics
Cytokines / immunology
Female
Humans
Immunity, Innate*
Male
Mice
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
Th1 Cells / immunology
Th1 Cells / pathology
Th2 Cells / immunology
Th2 Cells / pathology
Trichuriasis / genetics
Trichuriasis / immunology*
Trichuriasis / pathology
Trichuris / immunology*

Substances

Antigens, Helminth
Cytokines
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse