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Targeting monoamine oxidase to dampen NLRP3 inflammasome activation in inflammation

Cellular & Molecular Immunology volume 18, pages 1311–1313 (2021)Cite this article

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Inflammasomes represent protective weapons against pathogens and cellular damage, although their uncontrolled activation drives the progression of inflammatory, metabolic, and neurodegenerative disorders. Several signals activate the NLRP3 inflammasome, and a few studies have reported that mitochondrial reactive oxygen species (ROS) are involved in this process. However, the source of mitochondrial ROS and their specific role in NLRP3 triggering are unclear. Here, we show that H2O2 produced by the mitochondrial enzyme monoamine oxidase B (MAO-B) plays a nonredundant role in sustaining NLRP3 inflammasome activation. Mechanistically, MAO-B-dependent ROS formation caused mitochondrial dysfunction and NF-κB induction, resulting in NLRP3 and pro-IL-1β overexpression. Both in vitro and in vivo, MAO-B inhibition by rasagiline prevented IL-1β secretion, and MAO-B-deficient mice showed an impaired response to LPS-mediated endotoxemia. Our findings identify MAO-B as a specific producer of mitochondrial ROS fueling the NLRP3 inflammasome, thereby providing a basis for repurposing MAOB inhibitors to treat inflammasome-mediated pathologies.

Inflammation is a complex process orchestrated by the immune system in response to infection or tissue injury. Pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) are sensed by innate immune receptors, which trigger signaling pathways leading to the release of pro-inflammatory cytokines. The NLRP3 inflammasome, a key sensor of these signals, is a multiprotein platform generating active caspase-1, which converts IL-1β and IL-18 precursors into their mature active forms.1 NLRP3 inflammasome assembly results from a two-step process. The priming signal is induced by the toll-like receptor (TLR)/nuclear factor (NF)-κB pathway and upregulates the expression of proteins involved in the process, including NLRP3.1 The second signal results in the assembly of the multiprotein, active complex and seems to involve alterations in ion homeostasis, lysosomal rupture and mitochondrial ROS generation.1

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Acknowledgements

We thank P. Pelegrin (Instituto Murciano de Investigación Biosanitaria) and E. Latz (Institute of Innate Immunity) for the immortalized ASC-mCherry macrophages. We acknowledge Paola Brun, Ignazio Castagliuolo, Bianca Cali, Sara Zumerle, and Denis Martin-Valet for helpful discussion and Luisa Bin and Alberto Zecca for their contribution in performing experiments. The study was supported by ERC Steps 322823 to A.V. and IRP-PENTA Grant 18/07-1 to M.C.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy

    Ricardo Sánchez-Rodríguez, Fabio Munari, Francisca Venegas, Andrielly Agnellini, María Paulette Castro-Gil, Antonella Viola & Marcella Canton

  2. Fondazione Istituto di Ricerca Pediatrica Città della Speranza - IRP, 35129, Padova, Italy

    Ricardo Sánchez-Rodríguez, Fabio Munari, Roberta Angioni, Francisca Venegas, María Paulette Castro-Gil, Antonella Viola & Marcella Canton

  3. Venetian Institute of Molecular Medicine, Padova, Italy

    Andrielly Agnellini

  4. Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, CDMX, Mexico

    María Paulette Castro-Gil

  5. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy

    Alessandra Castegna

  6. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

    Roberto Luisetto

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  1. Ricardo Sánchez-Rodríguez
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  2. Fabio Munari
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  9. Antonella Viola
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  10. Marcella Canton
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Contributions

A.V. and M.C. designed the study, wrote the manuscript, and provided funds; R.S.R., F.M., A.A., F.V., and R.A. performed most of the experiments and the subsequent data analyses and prepared the figures; M.P.C.G. helped in performing experiments; R.L. performed in vivo experiments in the murine endotoxemia model; A.C. performed mass spectrometric analyses.

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Correspondence to Antonella Viola or Marcella Canton.

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Sánchez-Rodríguez, R., Munari, F., Angioni, R. et al. Targeting monoamine oxidase to dampen NLRP3 inflammasome activation in inflammation. Cell Mol Immunol 18, 1311–1313 (2021). https://doi.org/10.1038/s41423-020-0441-8

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