Illustrating the functional heterogeneity of M-MDSCs to predict sepsis outcomes

Guoxing Tang; Wenjin Xing; Lin Zhu; Yuting Lu; Kaishan Jiang; Shiji Wu; Ziyong Sun; Hongyan Hou; Liming Cheng; Fan He; Feng Wang

doi:10.1016/j.jare.2026.01.008

Illustrating the functional heterogeneity of M-MDSCs to predict sepsis outcomes

J Adv Res. 2026 Jan 3:S2090-1232(26)00008-1. doi: 10.1016/j.jare.2026.01.008. Online ahead of print.

Authors

Guoxing Tang¹, Wenjin Xing¹, Lin Zhu², Yuting Lu¹, Kaishan Jiang¹, Shiji Wu¹, Ziyong Sun¹, Hongyan Hou¹, Liming Cheng³, Fan He⁴, Feng Wang⁵

Affiliations

¹ Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: gchengliming2015@163.com.
⁴ Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: fhe@tjh.tjmu.edu.cn.
⁵ Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: fengwang@tjh.tjmu.edu.cn.

PMID: 41490841
DOI: 10.1016/j.jare.2026.01.008

Abstract

Introduction: Sepsis remains one of the leading causes of death worldwide. Monocytes play a pivotal role in sepsis due to their dual role in both pro-inflammation and immunosuppression. However, the phenotypic markers and developmental characteristics of immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSCs) in sepsis remain largely unknown.

Objectives: This study aimed to investigate the functional heterogeneity of M-MDSCs in sepsis.

Methods: The frequency of M-MDSCs was assessed for the prognosis of sepsis. Single-cell RNA sequencing was conducted on purified HLA-DR^highCD14⁺ and HLA-DR^lowCD14⁺ monocytes, respectively, from patients with sepsis to study their heterogeneity.

Results: We find that the frequency of M-MDSCs, as defined by classical markers, has limited value in the prognosis of sepsis due to their broad heterogeneity. Based on scRNA-seq analysis, M-MDSCs in sepsis are established as HLA-DR^lowCD14⁺ monocytes, which display high expression of RETN and low expression of HLA-DPB1. We further segregate M-MDSCs into five subsets: IL1R2_M-MDSC, THBS1_M-MDSC, S100A_M-MDSC, IFN-sti_M-MDSC, and PPBP_M-MDSC, with the first three subsets accounting for the majority of the population. Pro-inflammatory S100A_M-MDSC dominates early-stage population and is characterized by high expression of S100A. Middle-stage IL1R2_M-MDSC exhibits cytokine production, while THBS1_M-MDSC is associated with TGF-β signaling, revealing concurrent pro-inflammatory and immunosuppressive functions. In the late stage, both THBS1_M-MDSC and IL1R2_M-MDSC display immunosuppressive functions. Furthermore, our data suggest a metabolic shift from oxidative phosphorylation to fatty acid and amino acid biosynthesis as pro-inflammatory monocytes transition into immunosuppressive M-MDSCs. VSIG4, a novel functional marker of immunosuppressive M-MDSCs, is specifically expressed in THBS1_M-MDSC. Subsequently, our preliminary results suggest that the combined detection of surface VSIG4 and IL1R2 on HLA-DR^lowCD14⁺ monocytes shows potential for predicting sepsis outcomes.

Conclusion: This study illuminates the characteristics of M-MDSCs in sepsis, providing a new direction for disease prognosis.

Keywords: HLA-DR(low)CD14(+) monocytes; Heterogeneity; IL1R2; M-MDSCs; VSIG4.