Uncovering SPP1+ Macrophage, Neutrophils and Their Related Diagnostic Biomarkers in Intracranial Aneurysm and Subarachnoid Hemorrhage

Haipeng Jie; Boyang Wang; Jingjing Zhang; Xinzhao Wang; Xiang Song; Fan Yang; Changning Fu; Bo Dong; Feng Yan

doi:10.2147/JIR.S493828

Uncovering SPP1⁺ Macrophage, Neutrophils and Their Related Diagnostic Biomarkers in Intracranial Aneurysm and Subarachnoid Hemorrhage

J Inflamm Res. 2024 Nov 9:17:8569-8587. doi: 10.2147/JIR.S493828. eCollection 2024.

Authors

Haipeng Jie^{1

2}, Boyang Wang^{1

2}, Jingjing Zhang^{1

2}, Xinzhao Wang^{3

4}, Xiang Song³, Fan Yang⁵, Changning Fu⁶, Bo Dong^{1

2}, Feng Yan⁷

Affiliations

¹ Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
² Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
³ Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China.
⁴ REMEGEN, LTD, Yantai Economic & Technological Development Area, Yantai, People's Republic of China.
⁵ Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
⁶ Department of Critical Care Medicine, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
⁷ Department of Emergency Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.

Abstract

Background: Intracranial aneurysms (IA) frequently cause subarachnoid hemorrhage (SAH) and have poor prognosis. However, the molecular mechanisms and diagnostic biomarkers associated with IA and ruptured IA (rIA) remain poorly understood.

Methods: In this study, single-cell and transcriptome datasets were obtained from the GEO database. The cell populations were annotated to identify potential pathogenic subpopulations, followed by intercellular communication, pseudotime, and SCENIC analyses. Proteome-wide and transcriptome-wide Mendelian randomization (MR) analyses were conducted to identify risk factors for IA and SAH. The major pathological changes and diagnostic biomarkers of IA and SAH were identified based on the transcriptome datasets. A clinical cohort was established to identify the diagnostic biomarkers and validate the results.

Results: Macrophages and neutrophils were predominantly increased in IA and rIA tissues, and neutrophils were markedly upregulated in the blood of SAH patients. SPP1⁺ Macrophage was progressively elevated in aneurysms, promoting vascular smooth muscle cell (VSMC) phenotypic transformation and collagen matrix remodeling through the SPP1 and TGF-β pathways. Furthermore, HIF1α regulon was enriched in SPP1⁺ Macrophage, mediating inflammation and metabolic reprogramming, which contributed to IA progression. Integrated MR analysis identified CD36 as a risk factor for both IA and SAH, and it has been recognized as an effective blood biomarker for SAH. Neutrophils and their related indicators have emerged as excellent biomarkers of SAH in clinical cohorts.

Conclusion: This study highlighted the detrimental role of SPP1⁺ Macrophage in IA and SAH using single-cell sequencing and MR analyses. CD36 was identified as a risk factor for IA and SAH and was also an efficient blood biomarker for SAH. In a clinical cohort, neutrophils and related indicators were valuable for the early diagnosis of SAH.

Keywords: Mendelian randomization; SPP1+ Macrophage; intracranial aneurysm; neutrophils; single-cell sequencing.

Grants and funding

This work was supported by the National Natural Science Foundation of China [Nos. 81601721, 82070382 and 82371574], the Natural Science Foundation of Shandong Province [Nos. ZR2023MH306 and ZR2023MH026], and Taishan Scholars Program [No. ts 20190979].