Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function

Abstract

SUMMARY Natural killer (NK) cells are cytotoxic lymphocytes capable of rapid cytotoxicity, cytokine secretion, and clonal expansion. To sustain such energetically demanding processes, NK cells must increase their metabolic capacity upon activation. However, little is known about the metabolic requirements specific to NK cells in vivo . To gain greater insight, we investigated the role of aerobic glycolysis in NK cell function and demonstrate that their glycolytic rate increases rapidly following viral infection and inflammation, prior to that of CD8 + T cells. NK cell-specific deletion of lactate dehydrogenase A (LDHA) reveals that activated NK cells rely on this enzyme for both effector function and clonal proliferation, with the latter being shared with T cells. As a result, LDHA-deficient NK cells are defective in their anti-viral and anti-tumor protection. These findings suggest that aerobic glycolysis is a hallmark of NK cell activation that is key to their function.

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

“…In our mouse model, eNK are in contact with metformin during their antitumor function, which is not the case of the in vitro experiments. It is well-known that cytotoxic lymphocytes require a glycolytic metabolism for their maximal activity and educated NK cells display a high glycolytic rate [44], which is essential for their antitumor function [45]. Hence, metformin could affect NK cell metabolism in vivo impairing their function.…”

OLFM4 Regulates Lung Epithelial Cell Function in Sepsis-Associated ARDS/ALI via LDHA-Mediated NF-κB Signaling

“… 31 Natural killer cell-specific deletion of LDHA leads to defective anti-viral and anti-tumor activity of natural killer cells. 32 Moreover, during acute inflammation, inhibition of LDHA by specific inhibitors markedly reduced the number of neutrophils or ROS high neutrophils in blood. 30 Our results showed that the inhibition of LDHA effectively inhibited NF-κB activation in lung epithelial cells induced by LPS, indicating the potential role of LDHA in sepsis-associated ARDS.…”

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

“…While glycolysis may contribute to the inflammatory storm ( Wang et al, 2020b ; Virga et al, 2021 ), the absence of glycolysis can lead to the loss of antiviral function in NK cells. Sheppard et al (2021) found that LDHA-mediated aerobic glycolysis is a hallmark of NK cell activation. However, NK cells are more susceptible to MCNV infection in the absence of LDHA, caused by the decreased value-added rate and defective cytotoxicity of NK cells deficient in LDHA ( Sheppard et al, 2021 ).…”

“… Sheppard et al (2021) found that LDHA-mediated aerobic glycolysis is a hallmark of NK cell activation. However, NK cells are more susceptible to MCNV infection in the absence of LDHA, caused by the decreased value-added rate and defective cytotoxicity of NK cells deficient in LDHA ( Sheppard et al, 2021 ). Consistently, in early NK cells activated by IL-2/IL-12, mTOR1 significantly upregulated c-Myc and increased the rate of glycolysis, whereas NK cells lacking the c-Myc transcription factor downregulated IFNγ and cytolytic molecule granzyme B ( Loftus et al, 2018 ).…”

“…This effect initially occurs in tumor cells and is called the “Warburg” effect. Many studies have reported that aerobic glycolysis occurs in microglia ( Cheng et al, 2021a ; Wang et al, 2021a ), NK cells, and monocytes under different pathological conditions ( Cheng et al, 2016 ; Sheppard et al, 2021 ) and even virus-infected macrophages ( Wu et al, 2021 ). It is found that the serum and neutrophils of SARS-CoV-2 patients contain high lactate content, which is caused by elevated glycolysis ( McElvaney et al, 2020 ; Jia et al, 2021 ).…”