Identifying MS4A6A+ macrophages as potential contributors to the pathogenesis of nonalcoholic fatty liver disease, periodontitis, and type 2 diabetes mellitus

Junhao Wu; Jinsheng Wang; Caihan Duan; Chaoqun Han; Xiaohua Hou

doi:10.1016/j.heliyon.2024.e29340

Identifying MS4A6A⁺ macrophages as potential contributors to the pathogenesis of nonalcoholic fatty liver disease, periodontitis, and type 2 diabetes mellitus

Heliyon. 2024 Apr 9;10(8):e29340. doi: 10.1016/j.heliyon.2024.e29340. eCollection 2024 Apr 30.

Authors

Junhao Wu¹, Jinsheng Wang², Caihan Duan¹, Chaoqun Han¹, Xiaohua Hou¹

Affiliations

¹ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
² Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.

Abstract

Purpose: Concrete epidemiological evidence has suggested the mutually-contributing effect respectively between nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and periodontitis (PD); however, their shared crosstalk mechanism remains an open issue.

Method: The NAFLD, PD, and T2DM-related datasets were obtained from the NCBI GEO repository. Their common differentially expressed genes (DEGs) were identified and the functional enrichment analysis performed by the DAVID platform determined relevant biological processes and pathways. Then, the STRING database established a PPI network of such DEGs and topological analysis through Cytoscape 3.7.1 software along with the machine-learning analysis by the least absolute shrinkage and selection operator (LASSO) algorithm screened out hub characteristic genes. Their efficacy was validated by external datasets using the receiver operating characteristic (ROC) curve, and gene expression and location of the most robust one was determined using single-cell sequencing and immunohistochemical staining. Finally, the promising drugs were predicted through the CTD database, and the CB-DOCK 2 and Pymol platform mimicked molecular docking.

Result: Intersection of differentially expressed genes from three datasets identified 25 shared DEGs of the three diseases, which were enriched in MHC II-mediated antigen presenting process. PPI network and LASSO machine-learning analysis determined 4 feature genes, of which the MS4A6A gene mainly expressed by macrophages was the hub gene and key immune cell type. Molecular docking simulation chosen fenretinide as the most promising medicant for MS4A6A⁺ macrophages.

Conclusion: MS4A6A⁺ macrophages were suggested to be important immune-related mediators in the progression of NAFLD, PD, and T2DM pathologies.

Keywords: MS4A6A gene; Macrophages; Nonalcoholic fatty liver disease; Periodontitis; Type 2 diabetes mellitus.