IITZ-01 activates NLRP3 inflammasome by inducing mitochondrial damage

Wenxin Hu; Wei Jiang

doi:10.52396/JUSTC-2022-0090

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Open Access JUSTC Life Sciences

IITZ-01 activates NLRP3 inflammasome by inducing mitochondrial damage

Wenxin Hu,
Wei Jiang^,

The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China

Cite this:

https://doi.org/10.52396/JUSTC-2022-0090

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Author Bio:
Wenxin Hu is currently a master’s student under the supervision of Prof. Wei Jiang at the University of Science and Technology of China. Her research mainly focuses on NLRP3 inflammasome activation

Wei Jiang received her Ph.D. degree from the University of Science and Technology of China in 2007, and did postdoctoral research at the Ludwig Institute of Oncology in Switzerland from 2007 to 2011. She is currently a Professor at the Division of Life Sciences and Medicine of the University of Science and Technology of China. Her research interests include the role and mechanism of pattern recognition receptors in innate immune recognition, signal transduction and related diseases
Corresponding author: E-mail: ustcjw@ustc.edu.cn
Received Date: 13 June 2022
Accepted Date: 11 July 2022

Abstract Full text PDF

Abstract

Abstract

NLRP3 inflammasome can be activated by a variety of pathogen activators (including components of bacteria, viruses and fungi) or “danger signals” (including abnormal metabolites and environmental components), so its activation mechanism is extremely complex. IITZ-01 is a lysosomotropic molecule that can disrupt lysosomal functions. We found that IITZ-01 can activate inflammasome at a low concentration. Then, we determined that IITZ-01 is a specific activator of NLRP3 inflammasome through inflammasome stimulation, ELISA, Western blot and other experiments. Mechanistically, NLRP3 inflammasome activation induced by IITZ-01 is independent of direct binding and ion flow but dependent on mitochondrial damage and mROS accumulation. This study suggests that a lysosomotropic compound can activate NLRP3 inflammasome by impairing mitochondrial functions.

Graphical abstract

Molecular mechanism diagram of NLRP3 inflammasome activation induced by IITZ-01.

Abstract

NLRP3 inflammasome can be activated by a variety of pathogen activators (including components of bacteria, viruses and fungi) or “danger signals” (including abnormal metabolites and environmental components), so its activation mechanism is extremely complex. IITZ-01 is a lysosomotropic molecule that can disrupt lysosomal functions. We found that IITZ-01 can activate inflammasome at a low concentration. Then, we determined that IITZ-01 is a specific activator of NLRP3 inflammasome through inflammasome stimulation, ELISA, Western blot and other experiments. Mechanistically, NLRP3 inflammasome activation induced by IITZ-01 is independent of direct binding and ion flow but dependent on mitochondrial damage and mROS accumulation. This study suggests that a lysosomotropic compound can activate NLRP3 inflammasome by impairing mitochondrial functions.

Public Summary

IITZ-01 can activate inflammasome in BMDM cells.
IITZ-01 is a specific agonist of NLRP3 inflammasome.
IITZ-01 induces mitochondrial damage in BMDM cells, resulting in an increase in intracellular mROS, which can activate NLRP3 inflammasome.

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References(41)

References

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Figure 1. IITZ-01 induced caspase-1 activation and IL-1β production in BMDM cells. (a) ELISA of IL-1β in the supernatant from BMDM cells primed with LPS for 3 h and then stimulated with different doses of IITZ-01. (b, c) BMDM cells were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (b) ELISA of IL-1β in the supernatant. (c) Western blot of IL-1β, cleaved caspase-1 in culture supernatant (SN) and the precursors of IL-1β (pro-IL-1β), pro-caspase-1, β–actin in cell lysate (input). Nigericin was used as a positive control. Data are means ± SEMs (n=6 or 5).

Figure 2. IITZ-01 activated inflammasome in BMDM cells. (a, b) BMDM cells from WT or Casp1^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (a) ELISA of IL-1β in the supernatant. (b) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, and β–actin in cell lysate. (c, d) BMDM cells from WT or Asc^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (c) ELISA of IL-1β in the supernatant. (d) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, ASC, and β–actin in cell lysate. (e, f) BMDM cells from WT or Gsdmd^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (e) ELISA of IL-1β in the supernatant. (f) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, GSDMD, and β–actin in cell lysate. Nigericin was used as a positive control. Data are means ± SEMs (n=5). **P $ \leqslant $ 0.01, ***P $ \leqslant $ 0.001.

Figure 3. IITZ-01 activated NLRP3 inflammasome in BMDM cells. (a, b) BMDM cells from WT or Nlrp3^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (a) ELISA of IL-1β in the supernatant. (b) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, NLRP3, and β–actin in cell lysate. (c, d) BMDM cells were primed with LPS for 2 h, treated with different doses of CY-09 for 1 h, and then stimulated with IITZ-01 (2 μmol/L) for 3 h. (c) ELISA of IL-1β in the supernatant. (d) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, and β–actin in cell lysate. (e, f) BMDM cells were primed with LPS for 2 h, treated with different doses of MCC950 for 1 h, and then stimulated with IITZ-01 (2 μmol/L) for 3 h. (e) ELISA of IL-1β in the supernatant. (f) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, and β–actin in cell lysate. Nigericin was used as a positive control. Data are means ± SEMs (n=6, 5 or 5). *0.01 $\leqslant $ P $\leqslant $ 0.05, ***P $\leqslant $ 0.001, ns, not significant.

Figure 4. Inflammasome activation induced by IITZ-01 was independent of NLRC4, AIM2 and Pyrin. (a, b) BMDM cells from WT or Ipaf^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (a) ELISA of IL-1β in the supernatant. (b) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, and β–actin in cell lysate. (c, d) BMDM cells from WT or Aim2^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (c) ELISA of IL-1β in the supernatant. (d) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, and β–actin in cell lysate. (e, f) BMDM cells from WT or Pyrin^−/− mice were primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for different times. (e) ELISA of IL-1β in the supernatant. (f) Western blot of IL-1β and cleaved caspase-1 in SN and pro-IL-1β, pro-caspase-1, and β–actin in cell lysate. Nigericin was used as a positive control. Data are means ± SEMs (n=4, 4 or 5). ns, not significant.

Figure 5. NLRP3 inflammasome activation induced by IITZ-01 was independent of direct binding and ion flow. (a) Western blot of NLRP3, NEK7, pro-caspase-1, ASC and β-actin in BMDM cells treated with DARTS assays. (b, c) ELISA of IL-1β in the supernatant from BMDM cells primed with LPS for 3 h, treated with different doses of KCl, (b) and then stimulated with IITZ-01 (2 μmol/L) for 3 h or (c) stimulated with Nigericin (5 μmol/L) for 15 min. (d) ICP of intracellular potassium in BMDM cells of Nlrp3^−/− mice primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for 3 h or Nigericin (5 μmol/L) for 15 min. Data are means ± SEMs (n=6, 5 or 6).

Figure 6. IITZ-01 activated NLRP3 inflammasome by inducing mitochondrial damage and mROS accumulation. (a) Immunofluorescence of mitochondrial morphology in BMDM cells from WT and Nlrp3^−/− mice primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for 1 h or Nigericin (5 μmol/L) for 20 min. (b) Immunofluorescence of mROS in BMDM cells from WT and Nlrp3^−/− mice primed with LPS for 3 h and then stimulated with IITZ-01 (2 μmol/L) for 3 h or Nigericin (5 μmol/L) for 20 min. (c) ELISA of IL-1β in the supernatant from BMDM cells primed with LPS for 2 h, treated with different doses of MnTBAP for 1 h, and then stimulated with IITZ-01 (2 μmol/L) for 5 h. (d) Western blot of IL-1β and cleaved caspase-1 in the SN of BMDM cells primed with LPS for 2 h, treated with different doses of MnTBAP for 1 h, and then stimulated with IITZ-01 (2 μmol/L) for 3 h or Nigericin (5 μmol/L) for 15 min. Western blot of pro-IL-1β, pro-caspase-1 and β-actin in the lysate of those cells. Data are means ± SEMs (n=5). ***P $\leqslant $ 0.001.

[1]	Chauhan D, Vande Walle L, Lamkanfi M. Therapeutic modulation of inflammasome pathways. Immunological Reviews, 2020, 297 (1): 123–138. doi: 10.1111/imr.12908
[2]	McKee C M, Coll R C. NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma. Journal of Leukocyte Biology, 2020, 108 (3): 937–952. doi: 10.1002/JLB.3MR0720-513R
[3]	O’Connor W Jr, Harton J A, Zhu X, et al. Cutting edge: CIAS1/Cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-kB suppressive properties. The Journal of Immunology, 2003, 171 (12): 6329–6333. doi: 10.4049/jimmunol.171.12.6329
[4]	Bauernfeind F G, Horvath G, Stutz A, et al. Cutting edge: NF-kB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. The Journal of Immunology, 2009, 183 (2): 787–791. doi: 10.4049/jimmunol.0901363
[5]	He Y, Zeng M Y, Yang D, et al. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature, 2016, 530 (7590): 354–357. doi: 10.1038/nature16959
[6]	Schmid-Burgk J L, Chauhan D, Schmidt T, et al. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. Journal of Biological Chemistry, 2016, 291 (1): 103–109. doi: 10.1074/jbc.C115.700492
[7]	Broz P, Dixit V M. Inflammasomes: mechanism of assembly, regulation and signaling. Nature Reviews Immunology, 2016, 16 (7): 407–420. doi: 10.1038/nri.2016.58
[8]	Halle A, Hornung V, Petzold G C, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunology, 2008, 9 (8): 857–865. doi: 10.1038/ni.1636
[9]	Duewell P, Kono H, Rayner K J, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 2010, 464 (7293): 1357–1361. doi: 10.1038/nature08938
[10]	Stienstra R, Joosten L A, Koenen T, et al. The infammasome-mediated caspase-1 activation controls adipocyte diferentiation and insulin sensitivity. Cell Metabolism, 2010, 12 (6): 593–605. doi: 10.1016/j.cmet.2010.11.011
[11]	Stienstra R, van Diepen J A, Tack C J, et al. Infammasome is a central player in the induction of obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108 (37): 15324–15329. doi: 10.1073/pnas.1100255108
[12]	Toldo S, Abbate A. The NLRP3 infammasome in acute myocardial infarction. Nature Reviews Cardiology, 2018, 15 (4): 203–214. doi: 10.1038/nrcardio.2017.161
[13]	Joosten L A, Netea M G, Mylona E, et al. Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis& Rheumatism, 2010, 62 (11): 3237–3248. doi: 10.1002/art.27667
[14]	Hayward J A, Mathur A, Ngo C, et al. Cytosolic recognition of microbes and pathogens: Inflammasomes in action. Microbiology and Molecular Biology Reviews, 2018, 82 (4): e00015–e00018. doi: 10.1128/MMBR.00015-18
[15]	Rathinam V A K, Vanaja S K, Waggoner L, et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell, 2012, 150 (3): 606–619. doi: 10.1016/j.cell.2012.07.007
[16]	Muñoz-Planillo R, Kuffa P, Martínez-Colón G. K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity, 2013, 38 (6): 1142–1153. doi: 10.1016/j.immuni.2013.05.016
[17]	Franchi L, Muñoz-Planillo R, Núñez G. Sensing and reacting to microbes through the inflammasomes. Nature Immunology, 2012, 13 (4): 325–332. doi: 10.1038/ni.2231
[18]	Negash A A, Olson R M, Griffin S, et al. Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation. PLoS Pathogens, 2019, 15 (2): e1007593. doi: 10.1371/journal.ppat.1007593
[19]	Chen I Y, Moriyama M, Chang M F, et al. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Frontiers in Microbiology, 2019, 10: 50. doi: 10.3389/fmicb.2019.00050
[20]	Ichinohe T, Pang I K, Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nature Immunology, 2010, 11 (5): 404–410. doi: 10.1038/ni.1861
[21]	Kanneganti T D, Kundu M, Green D R. Innate immune recognition of mtDNA—An undercover signal? Cell Metabolism, 2015, 21 (6): 793–794. doi: 10.1016/j.cmet.2015.05.019
[22]	Shimada K, Crother T R, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 2012, 36 (3): 401–414. doi: 10.1016/j.immuni.2012.01.009
[23]	Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signaling pathways on ROS production. Nature Reviews Immunology, 2010, 10 (3): 210–215. doi: 10.1038/nri2725
[24]	Huang X P, Ludke A, Dhingra S, et al. Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneicbone marrow stem cells in the infarcted heart. FASEB Journal, 2016, 30 (9): 3069–3082. doi: 10.1096/fj.201600331R
[25]	Halle A, Hornung V, Petzold G C, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunology, 2008, 9 (8): 857–865. doi: 10.1038/ni.1636
[26]	Duewell P, Kono H, Rayner K J, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 2010, 464 (7293): 1357–1361. doi: 10.1038/nature08938
[27]	Shi F S, Yang L F, Kouadir M, et al. The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. Journal of Neuroinflammation, 2012, 9 (1): 73. doi: 10.1186/1742-2094-9-73
[28]	Hafner-Bratkovič I, Benčina M, Fitzgerald K A, et al. NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity. Cellular and Molecular Life Sciences, 2012, 69 (24): 4215–4228. doi: 10.1007/s00018-012-1140-0
[29]	Shi F S, Yang Y, Kouadir M, et al. Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia. Journal of Neuroimmunology, 2013, 260 (1/2): 121–125. doi: 10.1016/j.jneuroim.2013.04.016
[30]	Dostert C, Guarda G, Romero J F, et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One, 2009, 4 (8): e6510. doi: 10.1371/journal.pone.0006510
[31]	Nakahira K, Haspel J A, Rathinam V A K, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunology, 2011, 12 (3): 222–230. doi: 10.1038/ni.1980
[32]	Zhou R B, Yazdi A S, Menu P, et al. A role for mitochondria in NLRP3 inflammasome activation. Nature, 2011, 469 (7329): 221–225. doi: 10.1038/nature09663
[33]	Sanman L E, Qian Y, Eisele N A, et al. Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. eLife, 2016, 5: e13663. doi: 10.7554/eLife.13663
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IITZ-01 activates NLRP3 inflammasome by inducing mitochondrial damage

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