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HMGB1/TLR4 signaling pathway enhances abdominal aortic aneurysm progression in mice by upregulating necroptosis

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Abstract

Objective and design

The age-associated increases in aseptic inflammation and necroptosis are closely related to the emergence of various age-associated diseases.

Methods

In this study, the role of HMGB1/TLR4-induced necroptosis in abdominal aortic aneurysm (AAA) formation was investigated. First, the levels of sterile inflammatory mediators (HMGB1, TLR4) and necroptosis markers were measured in the abdominal aortas of young and old C57BL/6JNifdc mice. We observed that sterile inflammatory mediators and necroptosis markers were greatly increased in the abdominal aortas of old mice. Then, angiotensin II (Ang II)-induced AAA model in APOE−/− mice was used in this study. Mice AAA models were treated with the RIP1 inhibitor necrostatin-1 (Nec-1) or the TLR4 inhibitor TAK-242, respectively.

Results

We found that HMGB1, TLR4, and necroptosis markers were elevated in old mice compared with those in young mice. Same elevation was also found in the development of AAA in APOE−/− mice. In addition, the necroptosis inhibitor Nec-1 alleviated Ang II-induced AAA development while downregulating the expression of HMGB1/TLR4. After blocking TLR4 with TAK-242, the expression of necroptosis markers decreased significantly, and the progression of AAA was also alleviated in APOE−/− mice.

Conclusions

Our results indicated that HMGB1/TLR4-mediated necroptosis enhances AAA development in the Ang II-induced AAA model in APOE−/− mice and that TLR4 might be a potential therapeutic target for AAA management.

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Data availability

The authors will provide the raw data of this study unreservedly.

References

  1. Golledge J, et al. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 2006;26(12):2605–13.

    Article  CAS  PubMed  Google Scholar 

  2. Miyake T, Morishita R. Pharmacological treatment of abdominal aortic aneurysm. Cardiovasc Res. 2009;83(3):436–43.

    Article  CAS  PubMed  Google Scholar 

  3. Powell JT, Greenhalgh RM. Clinical practice. Small abdominal aortic aneurysms. N Engl J Med. 2003;348(19):1895–901.

    Article  PubMed  Google Scholar 

  4. Kent KC. Clinical practice. Abdominal aortic aneurysms. N Engl J Med. 2014;371(22):2101–8.

    Article  CAS  PubMed  Google Scholar 

  5. Golledge J. Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol. 2019;16(4):225–42.

    Article  PubMed  Google Scholar 

  6. Rouer M, et al. Rapamycin limits the growth of established experimental abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2014;47(5):493–500.

    Article  CAS  PubMed  Google Scholar 

  7. Xu B, et al. Angiotensin-converting enzyme 2, coronavirus disease 2019, and abdominal aortic aneurysms. J Vasc Surg. 2021;74(5):1740–51.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhang T, et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat Med. 2016;22(2):175–82.

    Article  PubMed  Google Scholar 

  9. Wang Q, et al. Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation. Circ Res. 2015;116(4):600–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Karunakaran D, et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci Adv. 2016;2(7):e1600224.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wang H, et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014;54(1):133–46.

    Article  CAS  PubMed  Google Scholar 

  12. He S, et al. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Sci U S A. 2011;108(50):20054–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fang H, et al. TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells. Cell Mol Immunol. 2014;11(2):150–9.

    Article  CAS  PubMed  Google Scholar 

  14. Lin SY, et al. Necroptosis promotes autophagy-dependent upregulation of DAMP and results in immunosurveillance. Autophagy. 2018;14(5):778–95.

    Article  CAS  PubMed  Google Scholar 

  15. Bai L, et al. M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis. Cell Death Dis. 2021;12(1):93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hong YP, et al. High-fat diet aggravates acute pancreatitis via TLR4-mediated necroptosis and inflammation in rats. Oxid Med Cell Longev. 2020;2020:8172714.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Huang Z, et al. Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell Death Differ. 2018;25(1):180–9.

    Article  CAS  PubMed  Google Scholar 

  18. Wang Z, et al. Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE(-/-) mice. Cell Biosci. 2019;9:68.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang Q, et al. Inhibition of receptor-interacting protein kinase 1 with necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model. Sci Rep. 2017;7:42159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gu HF, et al. Chronic unpredictable mild stress promotes atherosclerosis via HMGB1/TLR4-mediated downregulation of PPARγ/LXRα/ABCA1 in ApoE(-/-) mice. Front Physiol. 2019;10:165.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wheeler JB, et al. Relation of murine thoracic aortic structural and cellular changes with aging to passive and active mechanical properties. J Am Heart Assoc. 2015;4(3):e001744.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Johnston KW, et al. Suggested standards for reporting on arterial aneurysms. Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg. 1991;13(3):452–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ullery BW, Hallett RL, Fleischmann D. Epidemiology and contemporary management of abdominal aortic aneurysms. Abdom Radiol (NY). 2018;43(5):1032–43.

    Article  PubMed  Google Scholar 

  24. Ramella M, et al. Relevance of inflammation and matrix remodeling in abdominal aortic aneurysm (AAA) and popliteal artery aneurysm (PAA) progression. Am J Transl Res. 2018;10(10):3265–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Tan TW, et al. Outcomes of endovascular and open surgical repair of ruptured abdominal aortic aneurysms in elderly patients. J Vasc Surg. 2017;66(1):64–70.

    Article  PubMed  Google Scholar 

  26. Umebayashi R, Uchida HA, Wada J. Abdominal aortic aneurysm in aged population. Aging (Albany NY). 2018;10(12):3650–1.

    Article  PubMed  Google Scholar 

  27. Sakalihasan N, et al. Abdominal aortic aneurysms. Nat Rev Dis Primers. 2018;4(1):34.

    Article  PubMed  Google Scholar 

  28. Thompson SG, et al. Screening women aged 65 years or over for abdominal aortic aneurysm: a modelling study and health economic evaluation. Health Technol Assess. 2018;22(43):1–142.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Qiu H, et al. Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res. 2010;107(5):615–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang J, et al. Extracellular matrix disarray as a mechanism for greater abdominal versus thoracic aortic stiffness with aging in primates. Arterioscler Thromb Vasc Biol. 2016;36(4):700–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rodriguez-Menocal L, et al. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling. Am J Physiol Heart Circ Physiol. 2014;306(5):H641–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Albini PT, et al. Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms. Atherosclerosis. 2014;232(2):361–8.

    Article  CAS  PubMed  Google Scholar 

  33. Li M, Fukagawa NK. Age-related changes in redox signaling and VSMC function. Antioxid Redox Signal. 2010;12(5):641–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Figueiredo Borges L, et al. Collagen is reduced and disrupted in human aneurysms and dissections of ascending aorta. Hum Pathol. 2008;39(3):437–43.

    Article  PubMed  Google Scholar 

  35. Groeneveld ME, et al. The potential role of neutrophil gelatinase-associated lipocalin in the development of abdominal aortic aneurysms. Ann Vasc Surg. 2019;57:210–9.

    Article  PubMed  Google Scholar 

  36. Brubaker AL, Palmer JL, Kovacs EJ. Age-related dysregulation of inflammation and innate immunity: lessons learned from rodent models. Aging Dis. 2011;2(5):346–60.

    PubMed  PubMed Central  Google Scholar 

  37. Deepa SS, et al. Necroptosis increases with age and is reduced by dietary restriction. Aging Cell. 2018;17(4):e12770.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gupta SC, et al. Inflammation, a double-edge sword for cancer and other age-related diseases. Front Immunol. 2018;9:2160.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Joly L, et al. Influence of thoracic aortic inflammation and calcifications on arterial stiffness and cardiac function in older subjects. J Nutr Health Aging. 2016;20(3):347–54.

    Article  CAS  PubMed  Google Scholar 

  40. Wang S, Zhang Y. HMGB1 in inflammation and cancer. J Hematol Oncol. 2020;13(1):116.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Murakami Y, et al. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ. 2014;21(2):270–7.

    Article  CAS  PubMed  Google Scholar 

  42. Imhof BA, Jemelin S, Emre Y. Toll-like receptors elicit different recruitment kinetics of monocytes and neutrophils in mouse acute inflammation. Eur J Immunol. 2017;47(6):1002–8.

    Article  CAS  PubMed  Google Scholar 

  43. Elzinga S, et al. Toll-like receptors and inflammation in metabolic neuropathy; a role in early versus late disease? Exp Neurol. 2019;320:112967.

    Article  CAS  PubMed  Google Scholar 

  44. Peek V, et al. Age-dependent changes of adipokine and cytokine secretion from rat adipose tissue by endogenous and exogenous toll-like receptor agonists. Front Immunol. 2020;11:1800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. He S, et al. HMGB1 released by irradiated tumor cells promotes living tumor cell proliferation via paracrine effect. Cell Death Dis. 2018;9(6):648.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wang Y, et al. Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway. J Exp Clin Cancer Res. 2019;38(1):461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Matsunaga N, et al. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol. 2011;79(1):34–41.

    Article  CAS  PubMed  Google Scholar 

  48. Zhou T, et al. Identification of a novel class of RIP1/RIP3 dual inhibitors that impede cell death and inflammation in mouse abdominal aortic aneurysm models. Cell Death Dis. 2019;10(3):226.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (Nos. 81970400).

Author information

Author notes

  1. Shuai Bian and Le Yang contribute equally to this manuscript and share the first authorship.

Authors and Affiliations

  1. Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Shuai Bian, Le Yang, Lizhi Lv & Hai Yuan

  2. Binzhou Medical University, Binzhou, China

    Dongfang Zhao

  3. Department of Medical Ultrasound, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Tiezheng Wang

  4. Department of Invasive Therapy, Anqing Municipal Hospital (Anqing Hospital Affiliated to Anhui Medical University), Anqing, China

    Shuai Bian

  5. Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China

    Hai Yuan

  6. Department of Medical Ultrasound, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China

    Tiezheng Wang

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  1. Shuai Bian
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Contributions

SB and LY: contributed equally to this work and shared co-first authors. SB and LY: carried out the experiments and drafted the article. DZ and LL: collected and analyzed the data. TW: performed ultrasound examinations. HY: contributed to the conception and design of this study, executed article revision. All authors read and agreed with the final manuscript.

Corresponding author

Correspondence to Hai Yuan.

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The authors declare no competing interests.

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All animal experimental procedures were agreed with Shandong Provincial Hospital’s Committee of Animal Protection and Use.

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Responsible Editor: John Di Battista.

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Bian, S., Yang, L., Zhao, D. et al. HMGB1/TLR4 signaling pathway enhances abdominal aortic aneurysm progression in mice by upregulating necroptosis. Inflamm. Res. 72, 703–713 (2023). https://doi.org/10.1007/s00011-023-01694-3

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  • DOI: https://doi.org/10.1007/s00011-023-01694-3

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