Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling
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)]...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.587913/full |
| _version_ | 1818316936373600256 |
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| author | Kun Yang Kun Yang Jingjing Xu Min Fan Min Fan Fei Tu Fei Tu Xiaohui Wang Tuanzhu Ha Tuanzhu Ha David L. Williams David L. Williams Chuanfu Li Chuanfu Li |
| author_facet | Kun Yang Kun Yang Jingjing Xu Min Fan Min Fan Fei Tu Fei Tu Xiaohui Wang Tuanzhu Ha Tuanzhu Ha David L. Williams David L. Williams Chuanfu Li Chuanfu Li |
| author_sort | Kun Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T09:29:21Z |
| format | Article |
| id | doaj.art-749f370ebcba41b8a3a2504ba1a0643d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T09:29:21Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-749f370ebcba41b8a3a2504ba1a0643d2022-12-21T23:52:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-10-011110.3389/fimmu.2020.587913587913Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated SignalingKun Yang0Kun Yang1Jingjing Xu2Min Fan3Min Fan4Fei Tu5Fei Tu6Xiaohui Wang7Tuanzhu Ha8Tuanzhu Ha9David L. Williams10David L. Williams11Chuanfu Li12Chuanfu Li13Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesCenter of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesCenter of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesCenter of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesCenter of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesCenter of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesDepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesCenter of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United StatesRecent 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.587913/fulllactateyes associated protein (YAP)NF-kappa Binflammatory cytokinesmacrophages |
| spellingShingle | Kun Yang Kun Yang Jingjing Xu Min Fan Min Fan Fei Tu Fei Tu Xiaohui Wang Tuanzhu Ha Tuanzhu Ha David L. Williams David L. Williams Chuanfu Li Chuanfu Li Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling Frontiers in Immunology lactate yes associated protein (YAP) NF-kappa B inflammatory cytokines macrophages |
| title | Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling |
| title_full | Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling |
| title_fullStr | Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling |
| title_full_unstemmed | Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling |
| title_short | Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling |
| title_sort | lactate suppresses macrophage pro inflammatory response to lps stimulation by inhibition of yap and nf κb activation via gpr81 mediated signaling |
| topic | lactate yes associated protein (YAP) NF-kappa B inflammatory cytokines macrophages |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.587913/full |
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