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Inflammasome-independent role for NLRP3 in controlling innate anti-helminth immunity and tissue repair in the lung

By Alistair L Chenery, R Alhallaf, Z Agha, J Ajendra, JE Parkinson, MM Cooper, BHK Chan, RM Eichenberger, LA Dent, AAB Robertson, A Kupz, David Brough, Alex Loukas, Tara E. Sutherland, Judith E. Allen, PR Giacomin

Posted 13 Apr 2019
bioRxiv DOI: 10.1101/606392 (published DOI: 10.4049/jimmunol.1900640)

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. While inflammasome proteins such as NLRP3 have important pro-inflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected Nlrp3 −/− mice with N. brasiliensis . Unexpectedly, compared to 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 to WT mice. Notably, inflammasome activation was not evident early post-infection with N. brasiliensis and in contrast to Nlrp3 −/− mice, anti-helminth responses were unaffected in caspase-1/11 deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 can constrain lung neutrophilia and helminth killing and negatively regulate type 2 immune responses in an inflammasome-independent manner.

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