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

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.

Proteomic characterisation of perhexiline treatment on THP-1 M1 macrophage differentiation

“…Importantly we observed the downregulation of IL-1β, a key secreted protein for macrophage-mediated inflammation ( 51 ), both in the cell lysate (proteomics) and culture supernatant (ELISA). This immunosuppressive effect has been observed in mouse models of sepsis and atherosclerosis where PHX treatment inhibited inflammatory macrophage responses including IL-1β through the activation of KLF14 ( 25 , 26 ).…”

“…It has been suggested that PHX limits M2 macrophage polarization also by inhibiting this pathway ( 24 ). Furthermore, due to its ability to activate krüppel-like factor 14 (KLF14), PHX can mitigate macrophage mediated inflammation by ultimately downregulating IL-1β ( 25 , 26 ). These results suggest that PHX may be a suitable candidate drug for the management of diseases which involve dysregulation of macrophage phenotypes by ultimately shifting macrophage states.…”

Downregulation of KLF14 accelerated cellular senescence and aging

“…Previous studies have found that perhexiline can reduce the formation of atherosclerosis through the activation of KLF14 expression, and this strategy is currently used in the clinical treatment of cardiovascular diseases 40,24 . In addition, the activation of KLF14 by perhexiline conferred protection against sepsis in mice by inhibiting the inflammatory signaling pathway 64 . In our research, perhexiline, as a KLF14 agonist, enhanced cell proliferation, DNA synthesis, and DNA damage repair to inhibit cellular senescence by promoting the expression of POLD1.…”

Pulsed Electromagnetic Field (PEMF) Treatment Reduces Lipopolysaccharide-Induced Septic Shock in Mice

“…Caveolin 1 ( Cav1 ) plays a role in the inflammatory signal cascade in the murine LPS-induced septic shock model through the activation of NF-κB, and Cav1 −/− mice showed decreased mortality in response to LPS-induced septic shock [ 58 ]. Hexokinase 2 (encoded by Hk2 ) is a glycolytic enzyme that regulates the innate immune response through the secretion of inflammatory cytokines in LPS-stimulated macrophages [ 59 ]. Myeloperoxidase (encoded by Mpo ) is a key factor of the innate immune system mainly expressed in neutrophils, which is up-regulated in the LPS-stimulated immune responses of multiple organs resulting in tissue damage [ 60 ].…”