IL-1 and copper

We have heard about IL-1 as part of the Covid-19 cytokine storm. It is often labeled as a bad player in many varieties of inflammation. IL-1 is actually a family of small proteins, IL-1β being the most notorious, pro-inflammatory member. IL-1β is part of many inflammatory diseases. This post is not intended to offer medical advise but rather to give busy MDs some background information to continue their educations.

In a 1989 study looked at human rheumatoid arthritis patients who had relatively high levels of the copper/iron carrier ceruloplasmin but not erythrocyte Cu/Zn superoxide dismutase activity. Activity levels of Cu/Zn SOD increased after 4 weeks of copper supplementation (2 mg/day). For obvious reasons, the Cu/Zn SOD activity of inflamed tissues was not investigated. Cell cultured experiments with human fiborblasts revealed thatinterleukin-1 elevated Cu-Zn SOD activities in cultured fibroblasts.

IL-1 is produced by inflammasomes, protein assemblies that contain a protein called NLRP3/NALP3. In 2011 Bae and Park identified a disulfide bond between Cys8 and Cys108. The last few amino acids, of which was Cys108, were not resolved in this crystal structure.

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• Gram negative lipopolysaccharide, pathogen and danger associated molecular patterns (PAMP. DAMP), and such may be recognized by TLR4, which signals the nucleus to produce more inactive IL-1, NLRP3, and so on [2].
• Particular irritants from inorganic particles to beta amyloid deposits may be phagocytosed. When these phagosomes rupture, the protease cathepsin, and assorted irritants are released into the cell.
• Finally, reactive oxygen species may trigger inflammasome assembly.
• In addition to containing the pyrin domain with the redox sensitive disulfide bond, the NLRP3 protein belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs)[2]
• Adapter protein apoptosis-associated speck-like protein (ASC) A variety of signals cause NLRP3 to open up and bind ASC. This complex activates
• Procaspase-1 (green ellipse) is an and self inhibited inactive protease. Binding to the NLRP3/ASC complex allows self digestion of the inhibitor portion (rose circle)
• Active caspase-1 cleaves inactive proIL-1β to an active cytokine.

The paradoxical role of Cu/Zn SOD1

Chelation therapy not so fast!

Deigendesch and coworkers tested the hypothesis that copper causes inflammation. These authors demonstrated that NLRP3 inflammasome activation is blocked by removing copper from the active site of superoxide dismutase 1 with the copper chelator tetrathiomolybdate, [4] Inflammasome function is also impaired in Cu/Zn SOD deficient mice. Copper regulation was found in macrophages, but not monocytes, both in mice and humans. Chelation of bioavailable copper resulted in attenuated caspase-1–dependent inflammation. The authors reported reduced susceptibility to LPS-induced endotoxic shock. Because the chelator tetrathiomolybdate is clinically used to treat Wilson’s Disease, it might prove useful in inflammatory diseases involving the NLRP3 inflammasome.

Hydrogen peroxide has been described as a signalling molecule, or second messenger (5]. This disulfide bond of NRLP3 could be dependent on H₂O₂ from superoxide dismutase. While H₂O₂ reacts with thiols, it really is not as damaging as super oxide. Catalase also depletes hydrogen peroxide: H₂O₂ → 2 H₂O + O₂

The thiol of cysteine in proteins may form disulfide bonds with other protein scyteine thiols or with a low molecular weight thiol (PSSR, where R is anything and P is a protein. ) Any reduced low molecular weight thiol compound (R’SH) can take things back to normal.

protein − SSR + R^′SH ⇄ protein − SH + RSSR^′ [5]

Could N-acetyl cysteine be a source of reducing equivalents like the protein thioredoxin? Indeed, copper and N-acetyl cysteine have been suggested as therapies for Covid-19 in conjunction with standard treatments [6]

And finally, what about the niacin in Cu(I)NA₂? Could niacin be a precursor for more NADH + H⁺ that provides thioredoxin with reducing equivalents to inactivate the IL-1β producing inflammasome?

If you are a physician thinking about putting your patient on a chelation therapy to reduce inflammation… maybe not so fast. We need Cu/Zn SOD to scavenge super oxide. H₂O₂ is a less reactive messenger that tells the body there’s trouble via inflammasomes and IL1β. Your patient just needs reducing equivalents to turn the inflammasome off after it’s done it’s job.

References

1. DiSilvestro RA. (1989) Effects of inflammation on copper antioxidant enzyme levels.Adv Exp Med Biol. 1989;258:253-8
2. Bae JY , Park HH (2011) Crystal structure of NALP3 protein pyrin domain (PYD) and its implications in inflammasome assembly J Biol Chem 286(45):39528-36. [PMC free article]
3. Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. (2015) NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015 Nov 5;6:262 [Cross Ref]
4. Deigendesch N, Zychlinsky A, Meissner F. (2018) Copper Regulates the Canonical NLRP3 Inflammasome. J Immunol. 2018 Mar 1;200(5):1607-1617. [PMC free article]
5. Forman HJ, Maiorino M, Ursini F.(2010) Signaling functions of reactive oxygen species. Biochemistry. 49(5):835-42. [PMC free article]
6. Andreou A, Trantza S, Filippou D, Sipsas N, Tsiodras S. (2020)COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2. In Vivo. 2020 Jun;34(3 Suppl):1567-1588 [Cross Ref]
7. Freeman TL, Swartz TH. (2020) Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol. 2020 Jun 23;11:1518. [PMC free article]