NAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease

Randilea D Nichols,Jakob Von Moltke,Russell E Vance

doi:10.1038/s41467-017-02266-w

Abstract

Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can also drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Inflammasomes are broadly expressed in haematopoietic and non-haematopoietic cells and can trigger numerous downstream responses including production of IL-1β, IL-18, eicosanoids and pyroptotic cell death. Here we show a mouse model with endogenous NLRC4 inflammasome activation in Lysozyme2+ cells (monocytes, macrophages and neutrophils) in vivo exhibits a severe systemic inflammatory disease, reminiscent of human patients that carry mutant auto-active NLRC4 alleles. Interestingly, specific NLRC4 activation in Mrp8+ cells (primarily neutrophil lineage) is sufficient to cause severe inflammatory disease. Disease is ameliorated on an Asc−/− background, and can be suppressed by injections of anti-IL-1 receptor antibody. Our results provide insight into the mechanisms by which NLRC4 inflammasome activation mediates auto-inflammatory disease in vivo.

Highlights

Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood
Given that NLRC4 is functional in multiple cell types, including haematopoietic and intestinal epithelial cells, it remains unclear through which cell types NLRC4 activation can drive pathology
Experiments with FlaTox demonstrated that NAIP/NLRC4 activation in vivo can cause pathology in the absence of ‘priming’ or inflammasome-induced IL-1β/-1818

Summary

Introduction

Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Since bacterial infections typically activate numerous innate immune pathways, including TLRs, it has been difficult to separate the effects of NAIP/NLRC4 activation from the downstream pro-inflammatory effects of TLR activation It is not clear whether activation of endogenous wild-type NLRC4 alone would be sufficient to drive inflammation in vivo. We report the generation of a genetically engineered mouse that inducibly expresses the C-terminal 166 amino acids of Legionella pneumophila flagellin, fused to ovalbumin An advantage of these mice is that they permit the selective activation of the endogenous NAIP/NLRC4 inflammasome without the concomitant provision of additional exogenous ‘priming’ signals. These results suggest that neutrophil-dependent IL-1 is a major driver of inflammasomedependent auto-inflammatory disease in vivo

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