Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring

Pucino, Valentina; Certo, Michelangelo; Bulusu, Vinay; Cucchi, Danilo; Goldmann, Katriona; Pontarini, Elena; Haas, Robert; Jw, Smith; Headland, Sarah E.; Blighe, Kevin; Ruscica, Massimiliano; Humby, Frances; Lewis, Myles; Kamphorst, Jurre J.; Bombardieri, Michèle; Pitzalis, Costantino; Mauro, Claudio

doi:10.1016/j.cmet.2019.10.004

Cited by 322 publications

(293 citation statements)

References 100 publications

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“…Accumulation of lactate in the tissue microenvironment is also a feature of sepsis ( 10 ). It has been indicated that the physiological lactate concentration in blood or healthy tissues is approximately 1.5 – 3 mM ( 39 ), while the blood lactate levels in septic patients can reach over 20 mM ( 40 ). Remarkably, lactate levels can rise to 40 mM at the inflamed tissues ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Both peripheral and tissue resident RA CD4 + T cells have a unique metabolic signature (Weyand et al, 2017;Pucino et al, 2019). Indeed, RA CD4 + T cells exhibit an impairment in engaging glycolysis.…”

Section: Glucose Metabolismmentioning

confidence: 99%

Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

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Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipocytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.

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“…High concentrations of lactic acid are found in both blood and synovial fluid from inflamed joints in RA patients. Several studies have shown that lactate promotes the aggressive phenotype of FLS [174], the pro-inflammatory properties of macrophages [152][153][154], stimulates IL-17 secretion by CD4+ T cells and, at the same time, decrease CD4+T migration, which is related to the maintenance of a chronic inflammatory infiltrate [155,175]. Moreover, recently, a new lactate induced histone modification was described, lactylation, which correlates with the levels of lactate and is different from acetylation [176].…”

Section: Pro-inflammatory Metabolitesmentioning

confidence: 99%

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis

Coras

Murillo-Saich

Gumá

2020

Cells

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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA.

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Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring

Cited by 322 publications

References 100 publications

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

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

Metabolic Checkpoints in Rheumatoid Arthritis

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis

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