TY - JOUR
T1 - Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism
AU - Fang, Xia
AU - Zhao, Pei
AU - Gao, Shaoyong
AU - Liu, Dongmei
AU - Zhang, Song
AU - Shan, Mengtian
AU - Wang, Yuanyuan
AU - Herrmann, Joerg
AU - Li, Qiang
AU - Wang, Feilong
N1 - Publisher Copyright:
© 2023
PY - 2023/5/15
Y1 - 2023/5/15
N2 - Tumor cell-derived lactate has been recognized as the key driver of polarization in tumor-associated macrophages (TAMs). Intratumoral lactate can be transported into macrophages to fuel the TCA cycle, which is mediated by mitochondrial pyruvate carrier (MPC). At the heart of intracellular metabolism, MPC-mediated transport has been investigated in studies which suggested its role and importance in the process of TAMs polarization. However, previous studies relied on pharmacological inhibition instead of genetic approaches to evaluate the role of MPC in TAMs polarization. Here, we demonstrated that genetic depletion of MPC blocks the entry of lactate into mitochondria in macrophages. However, MPC-mediated metabolism was dispensable for IL-4/lactate-induced macrophages polarization as well as tumor growth. In addition, MPC depletion had no impact on hypoxia-inducible factor 1α (HIF-1α) stabilization and histone lactylation, both of which are required for TAMs polarization. Our study suggests that lactate itself, rather than its downstream metabolites, is responsible for TAMs polarization.
AB - Tumor cell-derived lactate has been recognized as the key driver of polarization in tumor-associated macrophages (TAMs). Intratumoral lactate can be transported into macrophages to fuel the TCA cycle, which is mediated by mitochondrial pyruvate carrier (MPC). At the heart of intracellular metabolism, MPC-mediated transport has been investigated in studies which suggested its role and importance in the process of TAMs polarization. However, previous studies relied on pharmacological inhibition instead of genetic approaches to evaluate the role of MPC in TAMs polarization. Here, we demonstrated that genetic depletion of MPC blocks the entry of lactate into mitochondria in macrophages. However, MPC-mediated metabolism was dispensable for IL-4/lactate-induced macrophages polarization as well as tumor growth. In addition, MPC depletion had no impact on hypoxia-inducible factor 1α (HIF-1α) stabilization and histone lactylation, both of which are required for TAMs polarization. Our study suggests that lactate itself, rather than its downstream metabolites, is responsible for TAMs polarization.
KW - Lactate
KW - Metabolism
KW - Mitochondrial pyruvate carrier
KW - Tumor-associated macrophages
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U2 - 10.1016/j.ijbiomac.2023.123810
DO - 10.1016/j.ijbiomac.2023.123810
M3 - Article
C2 - 36868333
AN - SCOPUS:85151456836
SN - 0141-8130
VL - 237
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
M1 - 123810
ER -