Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability

Abstract

Sepsis has a well-studied inflammatory phase, with a less-understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality; however, regulatory roles are unknown. We hypothesized that lactic acid (LA) contributes to the late phase and is not solely a consequence of bacterial infection. No studies have examined LA effects in sepsis models in vivo or a mechanism by which it suppresses LPS-induced activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined LA effects on the mast cell response to LPS. LA significantly suppressed LPS-induced cytokine production and NF-kB transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells. Suppression was MCT-1 dependent and reproducible with sodium lactate or formic acid. Further, LA significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and LA is a byproduct of this process, we examined changes in glucose metabolism. LA treatment reduced glucose uptake and lactate export during LPS stimulation. LA effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for LA effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting LA suppressive effects in the immunosuppressive phase of sepsis.

Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma

“…GPR81 also functions as a vital regulator of cell survival by inhibiting apoptosis and promoting cell survival ( 19 , 18 ). In the present study, it was hypothesized that the inhibition of GPR81 on cell proliferation would depend on apoptosis.…”

“…Previously, GPR81 was observed to be important in various types of cancer, participating in cell survival, metastasis, tumor growth and chemoresistance ( 16 – 18 ). GPR81 is activated by lactate, which inhibits the conversion of ATP to cAMP ( 19 ). MCT1 has a high affinity binding ability for lactate and is mainly responsible for lactate uptake ( 20 , 21 ).…”

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases

“…The activation of MCs is accompanied by a major metabolic reprogramming ( Table 3 ). Indeed, these metabolic processes regulate MCs inflammatory cytokines and ROS production and IGE-mediated degranulation ( 203 , 204 , 230 ). A role for adipokines in the regulation of MC function has been recently revealed ( 56 ).…”

Future Needs in Mast Cell Biology

“…These factors can alter the cellular responses of tumor-associated immune cells including macrophages [186,187], T cells [184,185] and mast cells [188]. For example, oxygen-glucose deprivation can induce mast cell degranulation and the release of histamine [189] and of IL-6 [190] and lactic acid can inhibit IL-33- and lipopolysaccharide (LPS)-mediated cytokine and chemokine production from mouse and human mast cells [188,191]. By contrast, another study reported that an acidic environment augments IgE-mediated production of IL-6 and IL-13 from mouse mast cells [192].…”