BMX Deletion Mitigates Neuroinflammation Induced by Retinal Ischemia/reperfusion Through Modulation of the AKT/ERK/STAT3 Signaling Cascade

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Mar 4

PMID 38434304

Authors

Guangyi Huang

Shaoyang Zhang

Jing Liao

Yuanjun Qin

Yiyi Hong

Qi Chen

Yunru Lin

Yue Li

Lin Lan

Wen Hu

Kongqian Huang

Fen Tang

Ningning Tang

Li Jiang

Chaolan Shen

Ling Cui

Haibin Zhong

Min Li

Peng Lu

Qinmeng Shu

Yantao Wei

Fan Xu

Affiliations

Soon will be listed here.

Abstract

Aims: Retinal ischemia/reperfusion (I/R) injury is implicated in the etiology of various ocular disorders. Prior research has demonstrated that bone marrow tyrosine kinase on chromosome X (BMX) contributes to the advancement of ischemic disease and inflammatory reactions. Consequently, the current investigation aims to evaluate BMX's impact on retinal I/R injury and clarify its implied mechanism of action.

Main Methods: This study utilized male and female systemic BMX knockout (BMX) mice to conduct experiments. The utilization of Western blot assay and immunofluorescence labeling techniques was employed to investigate variations in the expression of protein and tissue localization. Histomorphological changes were observed through H&E staining and SD-OCT examination. Visual function changes were assessed through electrophysiological experiments. Furthermore, apoptosis in the retina was identified using the TUNEL assay, as well as the ELISA technique, which has been utilized to determine the inflammatory factors level.

Key Findings: Our investigation results revealed that the knockdown of BMX did not yield a significant effect on mouse retina. In mice, BMX knockdown mitigated the negative impact of I/R injury on retinal tissue structure and visual function. BMX knockdown effectively reduced apoptosis, suppressed inflammatory responses, and decreased inflammatory factors subsequent to I/R injury. The outcomes of the current investigation revealed that BMX knockdown partially protected the retina through downregulating phosphorylation of AKT/ERK/STAT3 pathway.

Significance: Our investigation showed that BMX reduces AKT, ERK, and STAT3 phosphorylation, reducing apoptosis and inflammation. Thus, this strategy protected the retina from structural and functional damage after I/R injury.

References

Mukaida Y, Machida S, Masuda T, Tazawa Y . Correlation of retinal function with retinal histopathology following ischemia-reperfusion in rat eyes. Curr Eye Res. 2004; 28(6):381-9. DOI: 10.1080/02713680490503679. View

Tamagnone L, Lahtinen I, Mustonen T, Virtaneva K, Francis F, Muscatelli F . BMX, a novel nonreceptor tyrosine kinase gene of the BTK/ITK/TEC/TXK family located in chromosome Xp22.2. Oncogene. 1994; 9(12):3683-8. View

Yang F, Duan M, Zheng F, Yu L, Wang Y, Wang G . Fas signaling in adipocytes promotes low-grade inflammation and lung metastasis of colorectal cancer through interaction with Bmx. Cancer Lett. 2021; 522:93-104. DOI: 10.1016/j.canlet.2021.09.024. View

Grunert U, Martin P . Rod bipolar cells in the macaque monkey retina: immunoreactivity and connectivity. J Neurosci. 1991; 11(9):2742-58. PMC: 6575238. View

Weiss U . Inflammation. Nature. 2008; 454(7203):427. DOI: 10.1038/454427a. View

Janani R, Anitha R, Divya P, Chonche M, Baskaran V . Astaxanthin ameliorates hyperglycemia induced inflammation via PI3K/Akt-NF-κB signaling in ARPE-19 cells and diabetic rat retina. Eur J Pharmacol. 2022; 926:174979. DOI: 10.1016/j.ejphar.2022.174979. View

Chau C, Chen K, Deng H, Kim K, Hosoya K, Terasaki T . Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival and proliferation. Oncogene. 2002; 21(57):8817-29. DOI: 10.1038/sj.onc.1206032. View

Horwood N, Urbaniak A, Danks L . Tec family kinases in inflammation and disease. Int Rev Immunol. 2012; 31(2):87-103. DOI: 10.3109/08830185.2012.670334. View

Palmer C, Mutch B, Workman S, McDaid J, Horwood N, Foxwell B . Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NFkapp}B activity. Blood. 2007; 111(4):1781-8. DOI: 10.1182/blood-2007-07-102343. View

10.

Ye D, Xu Y, Shi Y, Fan M, Lu P, Bai X . Anti-PANoptosis is involved in neuroprotective effects of melatonin in acute ocular hypertension model. J Pineal Res. 2022; 73(4):e12828. DOI: 10.1111/jpi.12828. View

11.

Neves G, Lagnado L . The retina. Curr Biol. 1999; 9(18):R674-7. DOI: 10.1016/s0960-9822(99)80436-9. View

12.

Schmid H, Renner M, Dick H, Joachim S . Loss of inner retinal neurons after retinal ischemia in rats. Invest Ophthalmol Vis Sci. 2014; 55(4):2777-87. DOI: 10.1167/iovs.13-13372. View

13.

Guryanova O, Wu Q, Cheng L, Lathia J, Huang Z, Yang J . Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell. 2011; 19(4):498-511. PMC: 3076106. DOI: 10.1016/j.ccr.2011.03.004. View

14.

Yu A, Wang S, Xing Y, Han M, Shao K . 7,8-Dihydroxyflavone alleviates apoptosis and inflammation induced by retinal ischemia-reperfusion injury via activating TrkB/Akt/NF-kB signaling pathway. Int J Med Sci. 2022; 19(1):13-24. PMC: 8692126. DOI: 10.7150/ijms.65733. View

15.

Paeng S, Park W, Jung W, Lee D, Kim G, Choi Y . YCG063 inhibits Pseudomonas aeruginosa LPS-induced inflammation in human retinal pigment epithelial cells through the TLR2-mediated AKT/NF-κB pathway and ROS-independent pathways. Int J Mol Med. 2015; 36(3):808-16. DOI: 10.3892/ijmm.2015.2266. View

16.

Holopainen T, Rasanen M, Anisimov A, Tuomainen T, Zheng W, Tvorogov D . Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling. Proc Natl Acad Sci U S A. 2015; 112(42):13063-8. PMC: 4620883. DOI: 10.1073/pnas.1517810112. View

17.

Shi Y, Guryanova O, Zhou W, Liu C, Huang Z, Fang X . Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance. Sci Transl Med. 2018; 10(443). PMC: 6431250. DOI: 10.1126/scitranslmed.aah6816. View

18.

Qiu Y, Kung H . Signaling network of the Btk family kinases. Oncogene. 2000; 19(49):5651-61. DOI: 10.1038/sj.onc.1203958. View

19.

Yue J, Zhao X . GPR174 suppression attenuates retinopathy in angiotensin II (Ang II)-treated mice by reducing inflammation via PI3K/AKT signaling. Biomed Pharmacother. 2020; 122:109701. DOI: 10.1016/j.biopha.2019.109701. View

20.

Cenni B, Gutmann S, Gottar-Guillier M . BMX and its role in inflammation, cardiovascular disease, and cancer. Int Rev Immunol. 2012; 31(2):166-73. DOI: 10.3109/08830185.2012.663838. View