The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis

Yuan Yuan,Qing Tu,Tong Zhang,Jingbao Li,Yuqi Liu,Feng Chen,Lu Liu,Guangjian Fan,Liangfang Yao,Shiyuan Luo,Xinyi Zhang,Pengfei Liu

doi:10.1038/s41423-021-00806-5

Abstract

Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection. Glycolysis plays a role in maintaining the immune function of macrophages, which is crucial for severely septic patients. However, how the pathways that link glycolysis and macrophages are regulated is still largely unknown. Here, we provide evidence to support the function of KLF14, a novel Krüppel-like transcription factor, in the regulation of glycolysis and the immune function of macrophages during sepsis. KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis. Mechanistically, KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2. In addition, we confirmed that the expression of KLF14 was upregulated in septic patients. Furthermore, pharmacological activation of KLF14 conferred protection against sepsis in mice. These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.

Highlights

Sepsis is the leading cause of death worldwide and is defined as life-threatening multiple organ dysfunction caused by dysregulation of the host’s response to infection [1]
KLF14 is upregulated in macrophages in in vivo and in vitro sepsis models Previous observations have demonstrated that KLF14 is involved in T cell differentiation and that a lack of KLF14 results in protection against colitis, indicating that KLF14 is involved in the transplantation, we established murine endotoxemia and sepsis models
The results showed that the WT C57BL/6 mice receiving KLF14−/− bone marrow cell transplantation had a more severe inflammatory response in the lung tissues during sepsis, and the ELISA results of the serum

Summary

INTRODUCTION

Sepsis is the leading cause of death worldwide and is defined as life-threatening multiple organ dysfunction caused by dysregulation of the host’s response to infection [1]. The results showed that the expression of KLF14 increased in a time-dependent manner in RAW264.7 cells, THP-1-derived macrophages, and BMDMs in response to LPS stimulation (Fig. 1E–J) (Supplementary Fig. 1). We observed that the expression of KLF14 and F4/ 80 (a marker of macrophages) was upregulated in the lung tissues of septic mice (Fig. 1K) These results strongly suggest that KLF14 is involved in the inflammatory-immune regulation of macrophages during sepsis. Reported that KLF14 is a maternally expressed gene; we established female murine sepsis models, and the results showed that the deletion of KLF14 increased the inflammation level in female sepsis mice (Supplementary Fig. 3) These findings indicate that KLF14−/− murine sepsis models display an increased inflammatory response.

RESULTS

DISCUSSION

E Control