Identification of cell death-related biomarkers and immune infiltration in ischemic stroke between male and female patients

Front Immunol. 2023 Jun 26:14:1164742. doi: 10.3389/fimmu.2023.1164742. eCollection 2023.

Abstract

Background: Stroke is the second leading cause of death and the third leading cause of disability worldwide, with ischemic stroke (IS) being the most prevalent. A substantial number of irreversible brain cell death occur in the short term, leading to impairment or death in IS. Limiting the loss of brain cells is the primary therapy target and a significant clinical issue for IS therapy. Our study aims to establish the gender specificity pattern from immune cell infiltration and four kinds of cell-death perspectives to improve IS diagnosis and therapy.

Methods: Combining and standardizing two IS datasets (GSE16561 and GSE22255) from the GEO database, we used the CIBERSORT algorithm to investigate and compare the immune cell infiltration in different groups and genders. Then, ferroptosis-related differently expressed genes (FRDEGs), pyroptosis-related DEGs (PRDEGs), anoikis-related DEGs (ARDEGs), and cuproptosis-related DEGs (CRDEGs) between the IS patient group and the healthy control group were identified in men and women, respectively. Machine learning (ML) was finally used to generate the disease prediction model for cell death-related DEGs (CDRDEGs) and to screen biomarkers related to cell death involved in IS.

Results: Significant changes were observed in 4 types of immune cells in male IS patients and 10 types in female IS patients compared with healthy controls. In total, 10 FRDEGs, 11 PRDEGs, 3 ARDEGs, and 1 CRDEG were present in male IS patients, while 6 FRDEGs, 16 PRDEGs, 4 ARDEGs, and 1 CRDEG existed in female IS patients. ML techniques indicated that the best diagnostic model for both male and female patients was the support vector machine (SVM) for CDRDEG genes. SVM's feature importance analysis demonstrated that SLC2A3, MMP9, C5AR1, ACSL1, and NLRP3 were the top five feature-important CDRDEGs in male IS patients. Meanwhile, the PDK4, SCL40A1, FAR1, CD163, and CD96 displayed their overwhelming influence on female IS patients.

Conclusion: These findings contribute to a better knowledge of immune cell infiltration and their corresponding molecular mechanisms of cell death and offer distinct clinically relevant biological targets for IS patients of different genders.

Keywords: biomarker; cell death; gender difference; immune infiltration; ischemic stroke (IS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Brain
  • Brain Death
  • Cell Death
  • Female
  • Humans
  • Ischemic Stroke* / diagnosis
  • Male
  • Stroke*

Substances

  • Biomarkers

Grants and funding

This study was mainly supported by the National Key Research and Development (2022YFC2009700 and 2022YFC2009703), the National Natural Science Foundation of China (82102681), the Natural Science Foundation of Jiangsu Province (BK20210228), the China Postdoctoral Science Foundation (2022M720722), the Nanjing Health Science and Technology Development Special Fund Project (YKK20242), the Open Project of Jiangsu Health Development Research Center (JSHD2021028), the Project Foundation of Jiangsu Cancer Hospital (ZM201924), the Jiangsu Provincial Key Medical Discipline (ZDXK202249), and the Jiangsu Province Engineering Research Center of Health Emergency.