Brucella abortus nitric oxide metabolite regulates inflammasome activation and IL‐1β secretion in murine macrophages

• Published in: European journal of immunology 2019-07, Vol.49 (7), p.1023-1037
• Main Authors: Campos, Priscila Carneiro, Gomes, Marco Túlio Ribeiro, Marinho, Fábio Antônio Vitarelli, Guimarães, Erika Sousa, Cruz, Mariza Gabriela Faleiro, Oliveira, Sergio Costa
• Format: Article
• Language: English
• Subjects: Acidification; Animals; Bacteria; Brucella abortus; Brucella abortus - metabolism; Brucellosis - immunology; Caspase; Cell activation; Elk; immune evasion; Immune response; Immunity, Innate; Inflammasomes; Inflammasomes - metabolism; Innate immunity; Interleukin-1beta - metabolism; Macrophages; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Molecular modelling; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Potassium; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Purinergic P2X7 - genetics; ΔnarG mutant
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201848016

NLRP3 inflammasome is a protein complex crucial to caspase‐1 activation and IL‐1β and IL‐18 maturation. This receptor participates in innate immune responses to different pathogens, including the bacteria of genus Brucella. Our group recently demonstrated that Brucella abortus‐induced IL‐1β secretion involves NLRP3 inflammasome and it is partially dependent on mitochondrial ROS production. However, other factors could be involved, such as P2X7‐dependent potassium efflux, membrane destabilization, and cathepsin release. Moreover, there is increasing evidence that nitric oxide acts as a modulator of NLRP3 inflammasome. The aim of this study was to unravel the mechanism of NLRP3 inflammasome activation induced by B. abortus, as well as the involvement of bacterial nitric oxide (NO) as a modulator of this inflammasome pathway. We demonstrated that NO produced by B. abortus can be used by the bacteria to modulate IL‐1β secretion in infected murine macrophages. Additionally, our results suggest that B. abortus‐induced IL‐1β secretion depends on a P2X7‐independent potassium efflux, lysosomal acidification, cathepsin release, mechanisms clearly associated to NLRP3 inflammasome. In summary, our results help to elucidate the molecular mechanisms of NLRP3 activation and regulation during an intracellular bacterial infection. Brucella abortus activates the NLRP3 inflammasome via K+ efflux, lysosomal acidification, and cathepsin release, resulting in IL‐1β secretion in macrophages. Nitric oxide produced by bacterial denitrification inhibits NLRP3 inflammasome, decreasing IL‐1β secretion, and revealing a new mechanism of immune evasion by the pathogen.