CFLIP Regulates Alternative NLRP3 Inflammasome Activation in Human Monocytes

Overview

Journal Cell Mol Immunol

Date 2023 Aug 17

PMID 37591930

Authors

Yuhui Gao

Shi Yu

Mengdan Chen

Xun Wang

Lei Pan

Bin Wei

Guangxun Meng

Affiliations

Soon will be listed here.

Abstract

The innate immune responses, including inflammasome activation, are paramount for host defense against pathogen infection. In contrast to canonical and noncanonical inflammasome activation, in this study, heat-killed gram-negative bacteria (HK bacteria) were identified as single-step stimulators of the NLRP3 inflammasome in human monocytes, and they caused a moderate amount of IL-1β to be released from cells. Time course experiments showed that this alternative inflammasome response was finished within a few hours. Further analysis showed that the intrinsically limited NLRP3 inflammasome activation response was due to the negative regulation of caspase-8 by the short isoform of cFLIP (cFLIPs), which was activated by NF-κB. In contrast, overexpressed cFLIP, but not overexpressed cFLIP, inhibited the activation of caspase-8 and the release of IL-1β in response to HK bacteria infection in human monocytes. Furthermore, we demonstrated that TAK1 activity mediated the expression of cFLIPs and was upstream and essential for the caspase-8 cleavage induced by HK bacteria in human monocytes. The functional specificity of cFLIPs and TAK1 revealed unique responses of human monocytes to a noninvasive pathogen, providing novel insights into an alternative regulatory pathway of NLRP3 inflammasome activation.

Citing Articles

Raptinal: a powerful tool for rapid induction of apoptotic cell death.

Smith A, Hergenrother P Cell Death Discov. 2024; 10(1):371.

PMID: 39164225 PMC: 11335860. DOI: 10.1038/s41420-024-02120-1.

GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14.

Liu Q, Jiao L, Ye M, Ma Z, Yu J, Su L Cell Mol Immunol. 2024; 21(6):561-574.

PMID: 38570588 PMC: 11143353. DOI: 10.1038/s41423-024-01155-9.

New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation.

Kodi T, Sankhe R, Gopinathan A, Nandakumar K, Kishore A J Neuroimmune Pharmacol. 2024; 19(1):7.

PMID: 38421496 PMC: 10904444. DOI: 10.1007/s11481-024-10101-5.

Role for Caspase-8 in the Release of IL-1β and Active Caspase-1 from Viable Human Monocytes during Toxoplasma gondii Infection.

Pandori W, Matsuno S, Shin J, Kim S, Kao T, Mallya S J Immunol. 2024; 212(7):1161-1171.

PMID: 38372637 PMC: 11410338. DOI: 10.4049/jimmunol.2200513.

References

Ajibade A, Wang H, Wang R . Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 2013; 34(7):307-16. DOI: 10.1016/j.it.2013.03.007. View

Thornberry N, Bull H, Calaycay J, Chapman K, Howard A, Kostura M . A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992; 356(6372):768-74. DOI: 10.1038/356768a0. View

Safa A, Pollok K . Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers (Basel). 2012; 3(2):1639-71. PMC: 3281420. DOI: 10.3390/cancers3021639. View

Chang D, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart B, Yaish-Ohad S . c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 2002; 21(14):3704-14. PMC: 125398. DOI: 10.1093/emboj/cdf356. View

Xia S, Zhang Z, Magupalli V, Pablo J, Dong Y, Vora S . Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature. 2021; 593(7860):607-611. PMC: 8588876. DOI: 10.1038/s41586-021-03478-3. View

Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee B . Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018; 362(6418):1064-1069. PMC: 6522129. DOI: 10.1126/science.aau2818. View

Alves B, Tsui R, Almaden J, Shokhirev M, Davis-Turak J, Fujimoto J . IκBε is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol. 2014; 192(7):3121-32. PMC: 3965642. DOI: 10.4049/jimmunol.1302351. View

Yang J, Liu Z, Xiao T . Post-translational regulation of inflammasomes. Cell Mol Immunol. 2016; 14(1):65-79. PMC: 5214939. DOI: 10.1038/cmi.2016.29. View

Budd R, Yeh W, Tschopp J . cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol. 2006; 6(3):196-204. DOI: 10.1038/nri1787. View

10.

Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming M . Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science. 1997; 275(5297):206-9. DOI: 10.1126/science.275.5297.206. View

11.

Geserick P, Drewniok C, Hupe M, Haas T, Diessenbacher P, Sprick M . Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL- and CD95L-mediated apoptosis. Oncogene. 2007; 27(22):3211-20. DOI: 10.1038/sj.onc.1210985. View

12.

Krueger A, Schmitz I, Baumann S, Krammer P, Kirchhoff S . Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem. 2001; 276(23):20633-40. DOI: 10.1074/jbc.M101780200. View

13.

Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F . Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997; 386(6624):517-21. DOI: 10.1038/386517a0. View

14.

Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P . Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014; 514(7521):187-92. DOI: 10.1038/nature13683. View

15.

Unterreiner A, Rubert J, Kauffmann M, Fruhauf A, Heiser D, Erbel P . Pharmacological inhibition of IKKβ dampens NLRP3 inflammasome activation after priming in the human myeloid cell line THP-1. Biochem Biophys Res Commun. 2021; 545:177-182. DOI: 10.1016/j.bbrc.2021.01.051. View

16.

Kataoka T, Tschopp J . N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway. Mol Cell Biol. 2004; 24(7):2627-36. PMC: 371124. DOI: 10.1128/MCB.24.7.2627-2636.2004. View

17.

Martin-Sanchez F, Diamond C, Zeitler M, Gomez A, Baroja-Mazo A, Bagnall J . Inflammasome-dependent IL-1β release depends upon membrane permeabilisation. Cell Death Differ. 2016; 23(7):1219-31. PMC: 4946890. DOI: 10.1038/cdd.2015.176. View

18.

Ruhl S, Broz P . Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur J Immunol. 2015; 45(10):2927-36. DOI: 10.1002/eji.201545772. View

19.

Headland S, Norling L . The resolution of inflammation: Principles and challenges. Semin Immunol. 2015; 27(3):149-60. DOI: 10.1016/j.smim.2015.03.014. View

20.

Schmacke N, ODuill F, Gaidt M, Szymanska I, Kamper J, Schmid-Burgk J . IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity. 2022; 55(12):2271-2284.e7. PMC: 7614333. DOI: 10.1016/j.immuni.2022.10.021. View