Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling

Abstract

Recent evidence from cancer research indicates that lactate exerts a suppressive effect on innate immune responses in cancer. This study investigated the mechanisms by which lactate suppresses macrophage pro-inflammatory responses. Macrophages [Raw 264.7 and bone marrow derived macrophages (BMDMs)] were treated with LPS in the presence or absence of lactate. Pro-inflammatory cytokines, NF-κB and YAP activation and nuclear translocation were examined. Our results show that lactate significantly attenuates LPS stimulated macrophage TNF-α and IL-6 production. Lactate also suppresses LPS stimulated macrophage NF-κB and YAP activation and nuclear translocation in macrophages. Interestingly, YAP activation and nuclear translocation are required for LPS stimulated macrophage NF-κB activation and TNFα production. Importantly, lactate suppressed YAP activation and nuclear translocation is mediated by GPR81 dependent AMKP and LATS activation which phosphorylates YAP, resulting in YAP inactivation. Finally, we demonstrated that LPS stimulation induces an interaction between YAP and NF-κB subunit p65, while lactate decreases the interaction of YAP and NF-κB, thus suppressing LPS induced pro-inflammatory cytokine production. Our study demonstrates that lactate exerts a previously unknown role in the suppression of macrophage pro-inflammatory cytokine production via GPR81 mediated YAP inactivation, resulting in disruption of YAP and NF-κB interaction and nuclear translocation in macrophages.

Lactic acid in macrophage polarization: The significant role in inflammation and cancer

“…These findings suggested that GPR81 had a potential protective effect on atherosclerosis and targeting GPR81 may inhibit OSS-induced endothelial inflammation and dysfunction [99]. In 2020, KunYang discovered a new mechanism, found that lactic acid inhibited the activation of YAP and NF-κB during inflammation through GPR81-mediated signal transduction, and inhibited the pro-inflammatory response of macrophages stimulated by LPS [89].…”

“…The concentration of physiological lactic acid is approximately 1.5-3mM, inncreasing to 10 mM in blood and healthy tissues, and reaching as high as 25 mM after strenuous exercise. In inflammatory diseases, such as atherosclerotic plaques or rheumatic synovial fluid, the concentration of lactic acid can be around 10 mM, and in cancer tissues it can even reach to 20-40mM [19,89]. The accumulation of lactic acid had a great impact on the macrophages that had infiltrated and were staying in the tissue, which fur ther inf luenced disease progression.…”

Postbiotics, Metabolic Signaling, and Cancer

“…The endogenously produced lactate in the established tumors has been identified as a driver of angiogenesis, immune evasion, metastasis, and resistance to therapy [ 106 ]. On the other hand, lactate delivered by postbiotic supplementation may serve as an inhibitor of carcinogenesis through the maintenance of the epithelial integrity and downregulation of the tissue inflammation [ 11 , 107 , 108 , 109 , 110 , 111 ].…”

Bacterial and metabolic factors of staphylococcal planktonic and biofilm environments differentially regulate macrophage immune activation

“…In our study, the biofilm CM of SA and SE contained high amounts of bacterial lactate. In general, extracellular lactate is associated with an inhibitory effect on the pro-inflammatory immune response of macrophages (44)(45)(46). In a recent study, the group of Tammy Kielian compared the effects of biofilm environments from wild-type and a mutant SA strain deficient in the production of Land D-lactate on IL-10 induction (47).…”