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

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 haematop...

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Detalles Bibliográficos
Autores principales: Nichols, Randilea D., von Moltke, Jakob, Vance, Russell E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738432/
https://www.ncbi.nlm.nih.gov/pubmed/29263322
http://dx.doi.org/10.1038/s41467-017-02266-w
Descripción
Sumario: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.