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Nafamostat mesilate prevented caerulein-induced pancreatic injury by targeting HDAC6-mediated NLRP3 inflammasome activation

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Abstract

Objective

Nafamostat mesilate (NM), a synthetic broad-spectrum serine protease inhibitor, has been commonly used for treating acute pancreatitis (AP) and other inflammatory-associated diseases in some East Asia countries. Although the potent inhibitory activity against inflammation-related proteases (such as thrombin, trypsin, kallikrein, plasmin, coagulation factors, and complement factors) is generally believed to be responsible for the anti-inflammatory effects of NM, the precise target and molecular mechanism underlying its anti-inflammatory activity in AP treatment remain largely unknown.

Methods

The protection of NM against pancreatic injury and inhibitory effect on the NOD-like receptor protein 3 (NLRP3) inflammasome activation were investigated in an experimental mouse model of AP. To decipher the molecular mechanism of NM, the effects of NM on nuclear factor kappa B (NF-κB) activity and NF-κB mediated NLRP3 inflammasome priming were examined in lipopolysaccharide (LPS)-primed THP-1 cells. Additionally, the potential of NM to block the activity of histone deacetylase 6 (HDAC6) and disrupt the association between HDAC6 and NLRP3 was also evaluated.

Results

NM significantly suppressed NLRP3 inflammasome activation in the pancreas, leading to a reduction in pancreatic inflammation and prevention of pancreatic injury during AP. NM was found to interact with HDAC6 and effectively inhibit its function. This property allowed NM to influence HDAC6-dependent NF-κB transcriptional activity, thereby blocking NF-κB-driven transcriptional priming of the NLRP3 inflammasome. Furthermore, NM exhibited the potential to interfere the association between HDAC6 and NLRP3, impeding HDAC6-mediated intracellular transport of NLRP3 and ultimately preventing NLRP3 inflammasome activation.

Conclusions

Our current work has provided valuable insight into the molecular mechanism underlying the immunomodulatory effect of NM in the treatment of AP, highlighting its promising application in the prevention of NLRP3 inflammasome-associated inflammatory pathological damage.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Becker V. Pathological anatomy and pathogenesis of acute pancreatitis. World J Surg. 1981;5:303–13.

    Article  CAS  PubMed  Google Scholar 

  2. Liu R, Qi H, Wang J, Wang Y, Cui L, Wen Y, et al. Ulinastatin activates the renin-angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis. J Gastroenterol Hepatol. 2014;29:1328–37.

    Article  CAS  PubMed  Google Scholar 

  3. Ruud TE, Aasen AO, Stadaas JO, Aune S. Effects on peritoneal proteolysis and hemodynamics of prophylactic and therapeutic infusions of high doses of aprotinin in experimental acute pancreatitis. Scand J Gastroenterol. 1986;21:1011–7.

    Article  CAS  PubMed  Google Scholar 

  4. Wisner JR Jr, Ozawa S, Renner IG. The effects of nafamostat mesilate (FUT-175) on caerulein-induced acute pancreatitis in the rat. Int J Pancreatol. 1989;4:383–90.

    Article  CAS  PubMed  Google Scholar 

  5. Wisner JR Jr, Renner IG, Grendell JH, Niederau C, Ferrell LD. Gabexate mesilate (FOY) protects against ceruletide-induced acute pancreatitis in the rat. Pancreas. 1987;2:181–6.

    Article  CAS  PubMed  Google Scholar 

  6. Chen CC, Wang SS, Lee FY. Action of antiproteases on the inflammatory response in acute pancreatitis. JOP. 2007;8:488–94.

    PubMed  Google Scholar 

  7. Sundaram S, Gikakis N, Hack CE, Niewiarowski S, Edmunds LH Jr, Koneti Rao A, et al. Nafamostat mesilate, a broad spectrum protease inhibitor, modulates platelet, neutrophil and contact activation in simulated extracorporeal circulation. Thromb Haemost. 1996;75:76–82.

    Article  CAS  PubMed  Google Scholar 

  8. Duan HQ, Wu QL, Yao X, Fan BY, Shi HY, Zhao CX, et al. Nafamostat mesilate attenuates inflammation and apoptosis and promotes locomotor recovery after spinal cord injury. CNS Neurosci Ther. 2018;24:429–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yates AG, Weglinski CM, Ying Y, Dunstan IK, Strekalova T, Anthony DC. Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness. J Neuroinflammation. 2022;19:8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hoque R, Sohail M, Malik A, Sarwar S, Luo Y, Shah A, et al. TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology. 2011;141:358–69.

    Article  CAS  PubMed  Google Scholar 

  11. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018;17:588–606.

    Article  CAS  PubMed  Google Scholar 

  12. Luo ZL, Sun HY, Wu XB, Cheng L, Ren JD. Epigallocatechin-3-gallate attenuates acute pancreatitis induced lung injury by targeting mitochondrial reactive oxygen species triggered NLRP3 inflammasome activation. Food Funct. 2021;12:5658–67.

    Article  CAS  PubMed  Google Scholar 

  13. Pan X, Fang X, Wang F, Li H, Niu W, Liang W, et al. Butyrate ameliorates caerulein-induced acute pancreatitis and associated intestinal injury by tissue-specific mechanisms. Br J Pharmacol. 2019;176:4446–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ren JD, Ma J, Hou J, Xiao WJ, Jin WH, Wu J, et al. Hydrogen-rich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice. Mediators Inflamm. 2014;2014: 930894.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang L, Wang N, Shi G, Sun S. Follistatin-like 1 ameliorates severe acute pancreatitis associated lung injury via inhibiting the activation of NLRP3 inflammasome and NF-kappaB pathway. Am J Transl Res. 2022;14:4310–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Li C, Wang J, Fang Y, Liu Y, Chen T, Sun H, et al. Nafamostat mesilate improves function recovery after stroke by inhibiting neuroinflammation in rats. Brain Behav Immun. 2016;56:230–45.

    Article  CAS  PubMed  Google Scholar 

  17. Lin Y, Xu D, Gao F, Zheng X. Ulinastatin inhibits NLRP3-induced apoptosis in a PD cell model. Ann Transl Med. 2021;9:924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu Z, Zhu X, Xu C, Min F, Yu G, Chen C. Ulinastatin ameliorates the malignant progression of prostate cancer cells by blocking the RhoA/ROCK/NLRP3 pathway. Drug Dev Res. 2023;84:36–44.

    Article  CAS  PubMed  Google Scholar 

  19. Qiu J, Xiao X, Gao X, Zhang Y. Ulinastatin protects against sepsis‑induced myocardial injury by inhibiting NLRP3 inflammasome activation. Mol Med Rep 2021; 24.

  20. Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;215:44–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.

    Article  CAS  PubMed  Google Scholar 

  22. Noguchi S, Nakatsuka M, Konishi H, Kamada Y, Chekir C, Kudo T. Nafamostat mesilate suppresses NF-kappaB activation and NO overproduction in LPS-treated macrophages. Int Immunopharmacol. 2003;3:1335–44.

    Article  CAS  PubMed  Google Scholar 

  23. Xu S, Chen H, Ni H, Dai Q. Targeting HDAC6 attenuates nicotine-induced macrophage pyroptosis via NF-kappaB/NLRP3 pathway. Atherosclerosis. 2021;317:1–9.

    Article  CAS  PubMed  Google Scholar 

  24. Yang Q, Li S, Zhou Z, Fu M, Yang X, Hao K, et al. HDAC6 inhibitor Cay10603 inhibits high glucose-induced oxidative stress, inflammation and apoptosis in retinal pigment epithelial cells via regulating NF-kappaB and NLRP3 inflammasome pathway. Gen Physiol Biophys. 2020;39:169–77.

    Article  CAS  PubMed  Google Scholar 

  25. Magupalli VG, Negro R, Tian Y, Hauenstein AV, Di Caprio G, Skillern W, et al. HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science 2020; 369.

  26. Hsu CW, Shou D, Huang R, Khuc T, Dai S, Zheng W, et al. Identification of HDAC Inhibitors Using a Cell-Based HDAC I/II Assay. J Biomol Screen. 2016;21:643–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chang P, Li H, Hu H, Li Y, Wang T. The Role of HDAC6 in Autophagy and NLRP3 Inflammasome. Front Immunol. 2021;12: 763831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moreno-Gonzalo O, Ramirez-Huesca M, Blas-Rus N, Cibrian D, Saiz ML, Jorge I, et al. HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes. PLoS Pathog. 2017;13: e1006799.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liu L, Zhou X, Shetty S, Hou G, Wang Q, Fu J. HDAC6 inhibition blocks inflammatory signaling and caspase-1 activation in LPS-induced acute lung injury. Toxicol Appl Pharmacol. 2019;370:178–83.

    Article  CAS  PubMed  Google Scholar 

  30. Youn GS, Lee KW, Choi SY, Park J. Overexpression of HDAC6 induces pro-inflammatory responses by regulating ROS-MAPK-NF-kappaB/AP-1 signaling pathways in macrophages. Free Radic Biol Med. 2016;97:14–23.

    Article  CAS  PubMed  Google Scholar 

  31. Chen Q, Wang Y, Jiao F, Cao P, Shi C, Pei M, et al. HDAC6 inhibitor ACY1215 inhibits the activation of NLRP3 inflammasome in acute liver failure by regulating the ATM/F-actin signalling pathway. J Cell Mol Med. 2021;25:7218–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang Y, Li X, Chen Q, Jiao F, Shi C, Pei M, et al. Histone Deacetylase 6 Regulates the Activation of M1 Macrophages by the Glycolytic Pathway During Acute Liver Failure. J Inflamm Res. 2021;14:1473–85.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yan S, Wei X, Jian W, Qin Y, Liu J, Zhu S, et al. Pharmacological Inhibition of HDAC6 Attenuates NLRP3 Inflammatory Response and Protects Dopaminergic Neurons in Experimental Models of Parkinson’s Disease. Front Aging Neurosci. 2020;12:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Piippo N, Korhonen E, Hytti M, Skottman H, Kinnunen K, Josifovska N, et al. Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome. Sci Rep. 2018;8:6720.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell. 2005;18:601–7.

    Article  CAS  PubMed  Google Scholar 

  36. Aoyagi S, Archer TK. Modulating molecular chaperone Hsp90 functions through reversible acetylation. Trends Cell Biol. 2005;15:565–7.

    Article  CAS  PubMed  Google Scholar 

  37. Hou Q, Kan S, Wang Z, Shi J, Zeng C, Yang D, et al. Inhibition of HDAC6 With CAY10603 Ameliorates Diabetic Kidney Disease by Suppressing NLRP3 Inflammasome. Front Pharmacol. 2022;13: 938391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu J, Zhao X, Jiang X, He L, Wu X, Wang J, et al. Tubastatin A Improves Post-Resuscitation Myocardial Dysfunction by Inhibiting NLRP3-Mediated Pyroptosis Through Enhancing Transcription Factor EB Signaling. J Am Heart Assoc. 2022;11: e024205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82170660; 81570582) and Natural Science Foundation of Sichuan Province of China (No. 2022NSFSC0825).

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Author notes

  1. Peng Chen and Li-Jun Zhao have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Peng Chen & Jian-Dong Ren

  2. School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China

    Li-Jun Zhao, Ling Huang, Wen-Qi He, Ying-Rui Tang & Jian-Dong Ren

  3. Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Yi Liu

  4. Safety Evaluation Center, Sichuan Institute for Drug Control (Sichuan Testing Center of Medical Devices), Chengdu, 610097, China

    Peng Chen

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Contributions

J-DR secured the funding for the study. PC, L-JZ, and J-DR designed the experiments. PC, L-JZ, LH, W-QH, and Y-RT performed experiments and analyzed data. YL provided technical assistance in the experiments and revised the manuscript. J-DR drafted the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yi Liu or Jian-Dong Ren.

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The authors declare that there are no competing interests.

Ethics approval

The animal care and experimental protocols were approved by IACUC of the University of Electronic Science and Technology of China, in accordance with NIH guidelines for the Care and Use of Laboratory Animals.

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Responsible Editor: John Di Battista.

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Chen, P., Zhao, LJ., Huang, L. et al. Nafamostat mesilate prevented caerulein-induced pancreatic injury by targeting HDAC6-mediated NLRP3 inflammasome activation. Inflamm. Res. 72, 1919–1932 (2023). https://doi.org/10.1007/s00011-023-01794-0

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  • DOI: https://doi.org/10.1007/s00011-023-01794-0

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