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Journal Article

Copper Regulates the Canonical NLRP3 Inflammasome


Meissner,  Felix
Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society;

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Deigendesch, N., Zychlinsky, A., & Meissner, F. (2018). Copper Regulates the Canonical NLRP3 Inflammasome. Journal of Immunology, 200(5), 1607-1617. doi:10.4049/jimmunol.1700712.

Cite as: https://hdl.handle.net/21.11116/0000-0000-F57F-E
Inflammasomes are multimeric protein complexes that are activated through a NOD-like receptor and regulate the proteolytic activation of caspase-1 and cytokines, like IL-1 beta. The NLRP3 inflammasome is implicated in many human pathologies including infections, autoinflammatory syndromes, chronic inflammation, and metabolic diseases; however, the molecular mechanisms of activation are not fully understood. In this study we show that NLRP3 inflammasome activation requires intracellular copper. A clinically approved copper chelator, tetrathiomolybdate, inhibited the canonical NLRP3 but not the AIM2, NLRC4, and NLRP1 inflammasomes or NF-kappa B-dependent priming. We demonstrate that NLRP3 inflammasome activation is blocked by removing copper from the active site of superoxide dismutase 1, recapitulating impaired inflammasome function in superoxide dismutase 1-deficient mice. This regulation is specific to macrophages, but not monocytes, both in mice and humans. In vivo, depletion of bioavailable copper resulted in attenuated caspase-1-dependent inflammation and reduced susceptibility to LPS-induced endotoxic shock. Our results indicate that targeting the intracellular copper homeostasis has potential for the treatment of NLRP3-dependent diseases.