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.
| Original language | English |
|---|---|
| Pages (from-to) | 2724-2734 |
| Number of pages | 11 |
| Journal | Journal of Immunology |
| Volume | 203 |
| Issue number | 10 |
| Early online date | 4 Nov 2019 |
| DOIs | |
| Publication status | Published - 15 Nov 2019 |
Bibliographical note
Copyright © 2019 The Authors.Funding: This work was supported by the Wellcome Trust (106898/A/15/Z to J.E.A.), the Medical Research Council U.K. (MR/K01207X/1 [to J.E.A.] and MR/N003586/1 [to D.B.]), Australian National Health and Medical Research Council Grants 1117504 and 1132975 (to A.L.), the Queensland Department of Science, Information Technology and Innovation (to P.R.G.), and the Iraqi Cultural Attaché in Australia (to R.A.). T.E.S. was supported by Medical Research Foundation U.K. joint funding with Asthma U.K. (MRFAUK-2015-302).
Acknowledgement: We thank Vishva Dixit (Genentech) for the Nlrp3tm1Vmd mice. Thanks to Seth Masters (Walter and Eliza Hall Institute, Australia) for kindly providing B6-Nlrp3tm1Tsc/Siec and caspase-1/11 double-deficient mice. We thank the Flow Cytometry, Bioimaging, Genomic Technologies, and Biological Services core facilities at the University of Manchester.