SS31 Alleviates LPS-induced Acute Lung Injury by Inhibiting Inflammatory Responses Through the S100A8/NLRP3/GSDMD Signaling Pathway

Overview

Journal Eur J Med Res

Publisher Biomed Central

Specialty General Medicine

Date 2024 Nov 28

PMID 39609864

Authors

Peiyao Luo

Quankuan Gu

Jianpeng Wang

Xianyong Li

Nana Li

Wei Yang

Xianglin Meng

Mingyan Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an acute, diffuse, inflammatory lung injury caused by various endogenous or exogenous factors. It is currently widely recognized that an excessive inflammatory response resulting from immune imbalance constitutes a crucial pathogenic mechanism in ALI/ARDS. SS31 is a novel mitochondria-targeted antioxidant peptide. This article validates the role of SS31 in lipopolysaccharide (LPS)-induced ALI.

Methods: The study applied transcriptome sequencing, immunofluorescence, PCR, immunofluorescence and other methods to explore the mechanism of SS31 in LPS induced ALI.

Results: Transcriptome sequencing results indicate that LPS-induced ALI is closely associated with immune regulatory processes, the Toll-like receptor pathway, and the NF-κB signaling pathway. The role of SS31 in acute lung injury is closely related to biological processes, such as immune regulation and cell death. This study demonstrated that SS31 can inhibit the expression of inflammatory factors IL-6, IL-1β, IL-18, and TNF-α, and reduce the expression of pyroptosis-related proteins NLRP3, and GSDMD-N. Further analysis revealed that S100A8 may be a key gene in the effect of SS31. LPS stimulation leads to increased expression of S100A8, while SS31 decreases its expression. Recombinant protein S100A8 can attenuate the inhibitory effect of SS31 on IL-1β, IL-18, NLRP3, and GSDMD-N.

Conclusions: The research results indicate that SS31 may inhibit the activation of the NLRP3 inflammasome and suppress inflammatory responses by regulating S100A8, thereby alleviating LPS-induced ALI in mice; this process may be related to pyroptosis.

References

Fei L, Jingyuan X, Fangte L, Huijun D, Liu Y, Ren J . Preconditioning with rHMGB1 ameliorates lung ischemia-reperfusion injury by inhibiting alveolar macrophage pyroptosis via the Keap1/Nrf2/HO-1 signaling pathway. J Transl Med. 2020; 18(1):301. PMC: 7405465. DOI: 10.1186/s12967-020-02467-w. View

Anwar M, Shah M, Kim J, Choi S . Recent clinical trends in Toll-like receptor targeting therapeutics. Med Res Rev. 2018; 39(3):1053-1090. PMC: 6587958. DOI: 10.1002/med.21553. View

Kong X, Gao M, Liu Y, Zhang P, Li M, Ma P . GSDMD-miR-223-NLRP3 axis involved in B(a)P-induced inflammatory injury of alveolar epithelial cells. Ecotoxicol Environ Saf. 2022; 232:113286. DOI: 10.1016/j.ecoenv.2022.113286. View

Bellani G, Laffey J, Pham T, Fan E, Brochard L, Esteban A . Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016; 315(8):788-800. DOI: 10.1001/jama.2016.0291. View

Suo M, Qi Y, Liu L, Zhang C, Li J, Yan X . SS31 Alleviates Pressure Overload-Induced Heart Failure Caused by Sirt3-Mediated Mitochondrial Fusion. Front Cardiovasc Med. 2022; 9:858594. PMC: 9110818. DOI: 10.3389/fcvm.2022.858594. View

Ding P, Yang R, Li C, Fu H, Ren G, Wang P . Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway. Crit Care. 2023; 27(1):196. PMC: 10204208. DOI: 10.1186/s13054-023-04488-5. View

Liu B, He R, Zhang L, Hao B, Jiang W, Wang W . Inflammatory Caspases Drive Pyroptosis in Acute Lung Injury. Front Pharmacol. 2021; 12:631256. PMC: 7892432. DOI: 10.3389/fphar.2021.631256. View

He X, Qian Y, Li Z, Fan E, Li Y, Wu L . TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism. Sci Rep. 2016; 6:31663. PMC: 4985817. DOI: 10.1038/srep31663. View

Zhong L, Ren X, Ai Y, Liu Z . SS-31 Improves Cognitive Function in Sepsis-Associated Encephalopathy by Inhibiting the Drp1-NLRP3 Inflammasome Activation. Neuromolecular Med. 2022; 25(2):230-241. DOI: 10.1007/s12017-022-08730-1. View

10.

Wang Q, Long G, Luo H, Zhu X, Han Y, Shang Y . S100A8/A9: An emerging player in sepsis and sepsis-induced organ injury. Biomed Pharmacother. 2023; 168:115674. DOI: 10.1016/j.biopha.2023.115674. View

11.

Su M, Chen C, Li S, Li M, Zeng Z, Zhang Y . Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis. Nat Cardiovasc Res. 2022; 1(8):732-747. PMC: 9362711. DOI: 10.1038/s44161-022-00108-7. View

12.

Tang P, Mura M, Seth R, Liu M . Acute lung injury and cell death: how many ways can cells die?. Am J Physiol Lung Cell Mol Physiol. 2008; 294(4):L632-41. DOI: 10.1152/ajplung.00262.2007. View

13.

Huppert L, Matthay M, Ware L . Pathogenesis of Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med. 2019; 40(1):31-39. PMC: 7060969. DOI: 10.1055/s-0039-1683996. View

14.

He G, Chen K, Wang H, Li X, Li W, Liu L . Fudosteine attenuates acute lung injury in septic mice by inhibiting pyroptosis via the TXNIP/NLRP3/GSDMD pathway. Eur J Pharmacol. 2022; 926:175047. DOI: 10.1016/j.ejphar.2022.175047. View

15.

Chavez J, Tang X, Campbell M, Reyes G, Kramer P, Stuppard R . Mitochondrial protein interaction landscape of SS-31. Proc Natl Acad Sci U S A. 2020; 117(26):15363-15373. PMC: 7334473. DOI: 10.1073/pnas.2002250117. View

16.

Hong Q, Zhang Y, Lin W, Wang W, Yuan Y, Lin J . Negative Feedback of the cAMP/PKA Pathway Regulates the Effects of Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome Activation on Type II Alveolar Epithelial Cell Pyroptosis as a Novel Mechanism of BLM-Induced Pulmonary Fibrosis. J Immunol Res. 2022; 2022:2291877. PMC: 9410862. DOI: 10.1155/2022/2291877. View

17.

Ye Y, Yang Q, Wei J, Shen C, Wang H, Zhuang R . RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome. J Adv Res. 2024; 67():289-299. PMC: 11725153. DOI: 10.1016/j.jare.2024.01.017. View

18.

Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X . Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther. 2021; 6(1):128. PMC: 8005494. DOI: 10.1038/s41392-021-00507-5. View

19.

Wu Y, Hao C, Han G, Liu X, Xu C, Zou Z . SS-31 ameliorates hepatic injury in rats subjected to severe burns plus delayed resuscitation via inhibiting the mtDNA/STING pathway in Kupffer cells. Biochem Biophys Res Commun. 2021; 546:138-144. DOI: 10.1016/j.bbrc.2021.01.110. View

20.

Sauler M, Bazan I, Lee P . Cell Death in the Lung: The Apoptosis-Necroptosis Axis. Annu Rev Physiol. 2018; 81:375-402. PMC: 6598441. DOI: 10.1146/annurev-physiol-020518-114320. View