Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung

J Immunol. 2019 Nov 15;203(10):2724-2734. doi: 10.4049/jimmunol.1900640. Epub 2019 Oct 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 1 / physiology
  • Chemotaxis, Leukocyte
  • Eosinophilia / etiology
  • Eosinophilia / immunology
  • Furans / pharmacology
  • Heterocyclic Compounds, 4 or More Rings
  • Immunity, Innate
  • Indenes
  • Inflammasomes / physiology*
  • Interleukin-4 / pharmacology
  • Lectins / biosynthesis
  • Lectins / genetics
  • Lung / pathology
  • Lung / physiology
  • Lung Diseases, Parasitic / complications
  • Lung Diseases, Parasitic / immunology*
  • Lung Diseases, Parasitic / pathology
  • Lung Diseases, Parasitic / physiopathology
  • Macrophages, Alveolar / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology*
  • Neutrophils / immunology
  • Nippostrongylus / immunology*
  • Regeneration
  • Strongylida Infections / complications
  • Strongylida Infections / immunology*
  • Strongylida Infections / pathology
  • Strongylida Infections / physiopathology
  • Sulfonamides / pharmacology
  • Sulfones
  • Transcription, Genetic
  • beta-N-Acetylhexosaminidases / biosynthesis
  • beta-N-Acetylhexosaminidases / genetics

Substances

  • Furans
  • Heterocyclic Compounds, 4 or More Rings
  • Indenes
  • Inflammasomes
  • Lectins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Sulfonamides
  • Sulfones
  • Interleukin-4
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
  • Chil3 protein, mouse
  • beta-N-Acetylhexosaminidases
  • Casp1 protein, mouse
  • Caspase 1