ELK4 exerts opposite roles in cytokine/chemokine production and degranulation in activated mast cells

Yuji Huang; Zhehui Zhu; Weize Li; Yiqin Ge; Yanning Li; Juan Wang; Xia Peng; Lihui Lin; Jia Li; Chen-Ying Liu; Li Li

doi:10.3389/fimmu.2023.1171380

ELK4 exerts opposite roles in cytokine/chemokine production and degranulation in activated mast cells

Front Immunol. 2023 Jul 17:14:1171380. doi: 10.3389/fimmu.2023.1171380. eCollection 2023.

Authors

Yuji Huang¹, Zhehui Zhu², Weize Li¹, Yiqin Ge¹, Yanning Li¹, Juan Wang¹, Xia Peng¹, Lihui Lin¹, Jia Li¹, Chen-Ying Liu³, Li Li¹

Affiliations

¹ Department of Laboratory Medicine, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
² Department of Colorectal Surgery, Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Technology, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

The proliferative potential of mast cells after activation for 3-4h was found to be decreased, which suggests that mast cell degranulation and cell proliferation are differentially regulated. ELK4, a member of the ternary complex factor (TCF) subfamily of Ets transcription factors, is one of the downstream effectors of MAPK signaling that is critical for cell proliferation. And Elk4 has been identified to be vital for macrophage activation in response to zymosan and the transcriptional response to 12-O-tetrade canoyl phorbol-13-acetate (TPA) stimulation in fibroblast. However, the effect of ELK4 on the mast cell transcriptional response to FcϵRI and GPCR mediated activation and its potential functional significance in mast cells remain unclear. Here, we showed that ELK4 expression is downregulated in activated mast cells. Elk4 knockout suppresses cell proliferation and impedes the cell cycle in bone marrow-derived mast cells (BMMCs), which is associated with decreased transcription of cell cycle genes. Additionally, the transcriptional activation of cytokines and chemokines is diminished while mast cell degranulation is enhanced in Elk4 knockout BMMCs. Mechanistically, ELK4 might positively modulate Hdc, Ccl3 and Ccl4 transcription by interacting with MITF and negatively regulate the transcription of degranulation-related genes by complexing with SIRT6. Overall, our study identifies a new physiological role of the transcription factor ELK4 in mast cell proliferation and activation.

Keywords: ELK4; MITF; SIRT6; cell cycle; degranulation; mast cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chemokines / metabolism
Cytokines* / metabolism
Gene Expression Regulation
Mast Cells* / metabolism
Signal Transduction

Substances

Cytokines
Chemokines

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China [grant nos. 81871267, 82172916]; the Shanghai Shenkang Hospital Development Center [SHDC2020CR3007A]; and the Shanghai Committee of Science and Technology (19441904300).