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

By Alistair Chenery, Rafid Alhallaf, Zainab Agha, Jesuthas Ajendra, James Parkinson, Martha M Cooper, Brian HK Chan, Ramon M Eichenberger, Lindsay A Dent, Avril AB Robertson, Andreas Kupz, David Brough, Alex Loukas, Tara E Sutherland, Judith E Allen, Paul Giacomin

Posted 13 Apr 2019
bioRxiv DOI: 10.1101/606392

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 innate response to the infection. While NLRP3 has important pro-inflammatory functions in macrophages, its role during type 2 responses and repair is 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, there was a lack of inflammasome activation found early post-infection with N. brasiliensis and in contrast to Nlrp3-/- mice, anti-helminth responses were unaffected in Casp1/11-/- 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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