New advances in the activation mechanisms of NLRP3 inflammasome and its inhibitors

Abstract

Abstract: NLRP3 inflammasome is an intracellular multi-protein complex that can be activated by a variety of pathogens and endogenous pathogenic molecules and then leads to the release of cytokines, including interleukin-1β(IL-1β), IL-18 and causes, pyroptosis. It plays an important role in innate immunity. However, the over activation may lead chronic inflammation, which is closely related to the pathogenesis and development of numerous major diseases. Therefore, further investigation on the activation mechanisms of NLRP3 inflammasome is of great significance for the development of its specific inhibitors and the treatment of NLRP3-related diseases.

Key words: NLRP3 inflammasome, activating regulation, inhibitors, new advances

CLC Number:

R967

ZHOU Yong-ting, YE Cai-ying, ZHU Lei. New advances in the activation mechanisms of NLRP3 inflammasome and its inhibitors[J]. Basic & Clinical Medicine, 2020, 40(8): 1113-1118.

References

[1] Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to thera-peutics[J]. Nat Rev Immunol, 2019, 19:477-489.
[2] Chen J,Chen ZJ. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation[J]. Nature, 2018, 564: 71-76.
[3] Liu Q, Zhang D, Hu D, et al. The role of mitochondria in NLRP3 inflammasome activation[J]. Mol Immunol, 2018, 103: 115-124.
[4] Zhong Z, Liang S, Sanchez-Lopez E, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation[J]. Nature, 2018, 560: 198-203.
[5] Rao Z, Chen X, Wu J, et al. Vitamin D receptor inhibits NLRP3 activation by impeding its BRCC3-mediated deubiquitination[J]. Front Immunol, 2019, 10: 2783. doi:10.3389/fimmu.2019.02783.
[6] Han S, Lear TB, Jerome JA, et al. Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 Ligase[J]. J Biol Chem, 2015, 290: 18124-18133.
[7] Yan Y, Jiang W, Liu L, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome[J]. Cell, 2015, 160: 62-73.
[8] Song N, Liu ZS, Xue W, et al. NLRP3 phosphorylation is an essential priming event for inflammasome activation[J]. Mol Cell, 2017, 68: 185-197.
[9] Guo C, Xie S, Chi Z, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome[J]. Immunity, 2016, 45: 802-816.
[10] Shao L, Liu Y, Wang W, et al. SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation[J]. FASEB J, 2020, 34: 1497-1515.
[11] Mehto S, Jena KK, Nath P, et al. The Crohn's disease risk factor IRGM limits NLRP3 inflammasome activation by impeding its assembly and by mediating its selective autophagy[J]. Mol Cell, 2019, 73: 429-445.
[12] Houtman J, Freitag K, Gimber N, et al. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3[J]. EMBO J, 2019, 38: e99430. doi:10.15252/embj.201899430.
[13] Lang T, Lee JPW, Elgass K, et al. Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation[J]. Nat Commun, 2018, 9: 2223. doi:10.1038/s41467-018-04581-2.
[14] Li X, Thome S, Ma X, et al. MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism[J]. Nat Commun, 2017, 8: 15986. doi:10.1038/ncomms15986.
[15] Talty A, Deegan S, Ljujic M, et al. Inhibition of IRE1alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1beta[J]. Cell Death Dis, 2019, 10: 622. doi:10.1038/s41419-019-1847-z.
[16] Hughes MM, Hooftman A, Angiari S, et al. Glutathione transferase omega-1 regulates NLRP3 inflammasome activation through NEK7 deglutathionylation[J]. Cell Rep, 2019, 29: 151-161.
[17] Tapia-Abellan A, Angosto-Bazarra D, Martinez-Banaclocha H, et al. MCC950 closes the active conformation of NLRP3 to an inactive state[J]. Nat Chem Biol, 2019, 15: 560-564.
[18] Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases[J]. Nat Med, 2015, 21: 248-255.
[19] Vande Walle L, Stowe IB, Sacha P, et al. MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition[J]. PLoS Biol, 2019, 17: e3000354. doi: 10.1371/journal.pbio.3000354.
[20] Mangan MSJ, Olhava EJ, Roush WR, et al. Targeting the NLRP3 inflammasome in inflammatory diseases[J]. Nat Rev Drug Discov, 2018, 17: 588-606.
[21] Jiang H, He H, Chen Y, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders[J]. J Exp Med, 2017, 214: 3219-3238.
[22] Marchetti C, Swartzwelter B, Gamboni F, et al. OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation[J]. Proc Natl Acad Sci U S A, 2018, 115: E1530-E1539.
[23] Marchetti C, Swartzwelter B, Koenders MI, et al. NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis[J]. Arthritis Res Ther, 2018, 20: 169. doi:10.1186/s13075-018-1664-2.
[24] Huang Y, Jiang H, Chen Y, et al. Tranilast directly targets NLRP3 to treat inflammasome-driven diseases[J]. EMBO Mol Med, 2018, 10: e8689. doi:10.15252/emmm.201708689.
[25] He H, Jiang H, Chen Y, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity[J]. Nat Commun, 2018, 9: 2550. doi:10.1038/s41467-018-04947-6.