| First Author | Deigendesch N | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 5 | Pages | 1607-1617 |
| PubMed ID | 29358279 | Mgi Jnum | J:258416 |
| Mgi Id | MGI:6117927 | Doi | 10.4049/jimmunol.1700712 |
| Citation | Deigendesch N, et al. (2018) Copper Regulates the Canonical NLRP3 Inflammasome. J Immunol 200(5):1607-1617 |
| abstractText | 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-1beta. 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-kappaB-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. |
