PMID- 33123172 OWN - NLM STAT- MEDLINE DCOM- 20210716 LR - 20240429 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-kappaB Activation via GPR81-Mediated Signaling. PG - 587913 LID - 10.3389/fimmu.2020.587913 [doi] LID - 587913 AB - 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-kappaB and YAP activation and nuclear translocation were examined. Our results show that lactate significantly attenuates LPS stimulated macrophage TNF-alpha and IL-6 production. Lactate also suppresses LPS stimulated macrophage NF-kappaB and YAP activation and nuclear translocation in macrophages. Interestingly, YAP activation and nuclear translocation are required for LPS stimulated macrophage NF-kappaB activation and TNFalpha 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-kappaB subunit p65, while lactate decreases the interaction of YAP and NF-kappaB, 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-kappaB interaction and nuclear translocation in macrophages. CI - Copyright (c) 2020 Yang, Xu, Fan, Tu, Wang, Ha, Williams and Li. FAU - Yang, Kun AU - Yang K AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Xu, Jingjing AU - Xu J AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Fan, Min AU - Fan M AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Tu, Fei AU - Tu F AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Wang, Xiaohui AU - Wang X AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Ha, Tuanzhu AU - Ha T AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Williams, David L AU - Williams DL AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. FAU - Li, Chuanfu AU - Li C AD - Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. AD - Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States. LA - eng GR - R01 GM083016/GM/NIGMS NIH HHS/United States GR - R01 GM119197/GM/NIGMS NIH HHS/United States GR - R01 HL071837/HL/NHLBI NIH HHS/United States GR - R01 HL153270/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20201006 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Hcar1 protein, mouse) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Tnf protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (YAP-Signaling Proteins) RN - 0 (Yap1 protein, mouse) RN - 0 (interleukin-6, mouse) RN - 33X04XA5AT (Lactic Acid) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/immunology MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Cells, Cultured MH - Inflammation/immunology MH - Interleukin-6/immunology MH - Lactic Acid/*pharmacology MH - Lipopolysaccharides/pharmacology MH - Macrophages/*drug effects/immunology MH - Mice, Inbred C57BL MH - Mice, Knockout MH - NF-kappa B/immunology MH - Receptors, G-Protein-Coupled/immunology MH - Sepsis/immunology MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/immunology MH - YAP-Signaling Proteins PMC - PMC7573489 OTO - NOTNLM OT - NF-kappa B OT - inflammatory cytokines OT - lactate OT - macrophages OT - yes associated protein (YAP) EDAT- 2020/10/31 06:00 MHDA- 2021/07/17 06:00 PMCR- 2020/01/01 CRDT- 2020/10/30 05:54 PHST- 2020/07/27 00:00 [received] PHST- 2020/09/17 00:00 [accepted] PHST- 2020/10/30 05:54 [entrez] PHST- 2020/10/31 06:00 [pubmed] PHST- 2021/07/17 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.587913 [doi] PST - epublish SO - Front Immunol. 2020 Oct 6;11:587913. doi: 10.3389/fimmu.2020.587913. eCollection 2020.