Pyk2 regulates sepsis-induced lung injury via ferroptosis

Document Type : Original Article

Authors

1 Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Capital Medical University, Beijing, People’s Republic of China

2 Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China

3 Clinical Center for Medicine in Acute Infection,Capital Medical University, Beijing, People’s Republic of China

4 The Eighth medical center, PLA general hospital, Beijing, People’s Republic of China

Abstract

Objective(s): The onset of sepsis represents a hyper-inflammatory condition that can lead to organ failure and mortality. Recent findings suggest a potential beneficial effect of protein tyrosine kinase Pyk2 inhibitor on sepsis in a mouse model. In this study, we investigated the regulatory role of Pyk2 inhibitor in ferroptosis and sepsis-associated acute lung injury (ALI).
Materials and Methods: A Pyk2 inhibitor or a ferroptosis regulator were injected into mice sustaining sepsis-induced ALI and the effects on lung injury and pro-inflammatory response were evaluated. Clinically, Pyk2 expression was determined in serum samples of patients with sepsis. Further, the association between serum Pyk2 levels and clinical features was determined.
Results: Experimental mouse models revealed that treatment with Pyk2 inhibitor TAE226 can significantly alleviate lung injury, downregulate pro-inflammatory responses and decrease markers of ferroptosis, which were induced by LPS. Both upregulation and downregulation of ferroptosis can lead to the loss of TAE226 function, indicating that Pyk2 promotes inflammation via ferroptosis induction. Analysis of clinical samples revealed that the serum Pyk2 levels were significantly increased in patients with sepsis. The serum Pyk2 levels were associated with APACHE2 scores and 30-day mortality. Further, we found a negative correlation between serum Pyk2 and Fe3+ levels, which was consistent with the mechanism identified in the mouse model.
Conclusion: Pyk2 inhibitor of ferroptosis is a promising therapeutic candidate against sepsis-related ALI.

Keywords

Main Subjects

References

1. Wang J, Wang J, Wei B. The diagnostic value of Fe3+ and inflammation indicators in the death of sepsis patients: A retrospective study of 428 patients. Ther Clin Risk Manag 2021;17:55-63.
2. He R, Liu B, Xiong R, Geng B, Meng H, Lin W, et al. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury. Cell Death Discov 2022;8:43-53.
3. Kumar V. Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury. Front Immunol 2020;11:1722-1742.
4. Wang YM, Ji R, Chen WW, Huang SW, Zheng YJ, Yang ZT, et al. Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4/NF-κB pathway. Drug Des Devel Ther 2019;13:3391-3404.
5. Wooff Y, Man SM, Aggio-Bruce R, Natoli R, Fernando N. IL-1 family members mediate cell death, inflammation and angiogenesis in retinal degenerative diseases. Front Immunol 2019;10:1618-1638.
6. Fulda S. Cell death and survival signaling in oncogenesis. Klin Padiatr 2010;222:340-344.
7. Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem 2018;46:1650-1667.
8. Zhang ZT, Zhang DY, Xie K, Wang CJ, Xu F. Luteolin activates Tregs to promote IL-10 expression and alleviating caspase-11-dependent pyroptosis in sepsis-induced lung injury. Int Immunopharmacol 2021;99:107914.
9. Robinson N, Ganesan R, Hegedűs C, Kovács K, Kufer TA, Virág L. Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos. Redox Biol 2019;26:101239-101246. 
10. Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, et al. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol 2020;13:110-127.
11. D’Arcy MS. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019;43:582-592.
12. Zhang Y, Fu X, Jia J, Wikerholmen T, Xi K, Kong Y, et al. Glioblastoma therapy using codelivery of cisplatin and glutathione peroxidase targeting sirna from iron oxide nanoparticles. ACS Appl Mater Interfaces 2020;12:43408-43421.
13. Shen T, Guo Q. Role of Pyk2 in human cancers. Med Sci Monit 2018;24:8172-8182. 
14. Alves GF, Aimaretti E, Einaudi G, Mastrocola R, de Oliveira JG, Collotta D, et al. Pharmacological inhibition of FAK-Pyk2 pathway protects against organ damage and prolongs the survival of septic mice. Front Immunol 2022;13:837180-837193. 
15. Duan Y, Learoyd J, Meliton AY, Leff AR, Zhu X. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury. Respir Res 2012;13:4-13.
16. Yao X, Zhang Y, Hao J, Duan HQ, Zhao CX, Sun C, et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res 2019;14:532-541. 
17. Meads MB, Fang B, Mathews L, Gemmer J, Nong L, Rosado-Lopez I, et al. Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. Oncogene 2016;35:2723-2734.
18. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci 2019;20:5376-5406. 
19. Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, et al. Sepsis-induced immunosuppression: Mechanisms, diagnosis and current treatment options. Mil Med Res 2022;9:56-74. 
20. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 2020;395:200-211. 
21. Momin AA, Mendes T, Barthe P, Faure C, Hong S, Yu P, et al. PYK2 senses calcium through a disordered dimerization and calmodulin-binding element. Commun Biol. 2022;5:800-814.
22. Lim ST, Miller NL, Nam JO, Chen XL, Lim Y, Schlaepfer DD. Pyk2 inhibition of p53 as an adaptive and intrinsic mechanism facilitating cell proliferation and survival. J Biol Chem 2010;285:1743-1753. 
23. Conte A, Kisslinger A, Procaccini C, Paladino S, Oliviero O, de Amicis F, et al. Convergent effects of resveratrol and PYK2 on prostate cells. Int J Mol Sci 2016;17:1542-1563. 
24. Wang D, Lin Y, Xu F, Zhang H, Zhu X, Liu Z, et al. SIRPα maintains macrophage homeostasis by interacting with PTK2B kinase in Mycobacterium tuberculosis infection and through autophagy and necroptosis. EBioMedicine 2022;85:104278-104302. 
25. He R, Liu B, Xiong R, Geng B, Meng H, Lin W, et al. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury. Cell Death Discov 2022;8:43-53.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 11
November 2023
Pages 1283-1290

Files

Share

How to cite

Statistics