Chenery, Alistair L., Alhallaf, Rafid, Agha, Zainab, Ajendra, Jesuthas, Parkinson, James E., Cooper, Martha M., Chan, Brian H. K., Eichenberger, Ramon M., Dent, Lindsay A., Robertson, Avril A. B., Kupz, Andreas, Brough, David, Loukas, Alex, Sutherland, Tara E., Allen, Judith E., and Giacomin, Paul R. (2019) Inflammasome-independent role for NLRP3 in controlling innate antihelminth immunity and tissue repair in the lung. Journal of Immunology, 203 (10). 1900640. pp. 2724-2734.

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Abstract

Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, Nippostrongylus brasiliensis, suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. Although inflammasome proteins such as NLRP3 have important proinflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected Nlrp3 -/- mice with N. brasiliensis Unexpectedly, compared with wild-type (WT) mice, infected Nlrp3 -/- mice had increased neutrophilia and eosinophilia, correlating with enhanced worm killing but at the expense of increased tissue damage and delayed lung repair. Transcriptional profiling showed that infected Nlrp3 -/- mice exhibited elevated type 2 gene expression compared with WT mice. Notably, inflammasome activation was not evident early postinfection with N. brasiliensis, and in contrast to Nlrp3 -/- mice, antihelminth responses were unaffected in caspase-1/11-deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 has a role in constraining lung neutrophilia, helminth killing, and type 2 immune responses in an inflammasome-independent manner.

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