دورية أكاديمية
أعرض في EDS

MEK1/2-PKM2 Pathway Modulates the Immunometabolic Reprogramming of Proinflammatory Allograft-infiltrating Macrophages During Heart Transplant Rejection.

التفاصيل البيبلوغرافية
العنوان: MEK1/2-PKM2 Pathway Modulates the Immunometabolic Reprogramming of Proinflammatory Allograft-infiltrating Macrophages During Heart Transplant Rejection.
المؤلفون: Chen Z; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Li Y; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Niu Y; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Zhang X; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Yu J; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Cui J; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Ran S; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Wang S; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Ye W; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Xia J; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Wuhan, China.; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.; Institute of Translational Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Wu J; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Wuhan, China.; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.; Institute of Translational Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
المصدر: Transplantation [Transplantation] 2024 May 01; Vol. 108 (5), pp. 1127-1141. Date of Electronic Publication: 2024 Jan 19.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0132144 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1534-6080 (Electronic) Linking ISSN: 00411337 NLM ISO Abbreviation: Transplantation Subsets: MEDLINE
أسماء مطبوعة: Publication: Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Williams & Wilkins.
مواضيع طبية MeSH: Heart Transplantation*/adverse effects , Graft Rejection*/immunology , Graft Rejection*/metabolism , Graft Rejection*/pathology , Graft Rejection*/genetics , Macrophages*/immunology , Macrophages*/metabolism , Mice, Knockout* , MAP Kinase Kinase 2*/metabolism , MAP Kinase Kinase 1*/metabolism , MAP Kinase Kinase 1*/genetics, Animals ; Mice ; Thyroid Hormone-Binding Proteins ; Mice, Inbred C57BL ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Male ; Signal Transduction ; Carrier Proteins/metabolism ; Carrier Proteins/genetics ; Glycolysis ; Pyruvate Kinase/metabolism ; Pyruvate Kinase/genetics ; Disease Models, Animal ; Phenotype ; Allografts
مستخلص: Background: Emerging evidence has highlighted the role of macrophages in heart transplant rejection (HTR). However, the molecular signals modulating the immunometabolic phenotype of allograft-infiltrating macrophages (AIMs) during HTR remain unknown.
Methods: We analyzed single-cell RNA sequencing data from cardiac graft-infiltrating immunocytes to characterize the activation patterns and metabolic features of AIMs. We used flow cytometry to determine iNOS and PKM2 expression and MEK/ERK signaling activation levels in AIMs. We then generated macrophage-specific Mek1/2 knockout mice to determine the role of the MEK1/2-PKM2 pathway in the proinflammatory phenotype and glycolytic capacity of AIMs during HTR.
Results: Single-cell RNA sequencing analysis showed that AIMs had a significantly elevated proinflammatory and glycolytic phenotype. Flow cytometry analysis verified that iNOS and PKM2 expressions were significantly upregulated in AIMs. Moreover, MEK/ERK signaling was activated in AIMs and positively correlated with proinflammatory and glycolytic signatures. Macrophage-specific Mek1/2 deletion significantly protected chronic cardiac allograft rejection and inhibited the proinflammatory phenotype and glycolytic capacity of AIMs. Mek1/2 ablation also reduced the proinflammatory phenotype and glycolytic capacity of lipopolysaccharides + interferon-γ-stimulated macrophages. Mek1/2 ablation impaired nuclear translocation and PKM2 expression in macrophages. PKM2 overexpression partially restored the proinflammatory phenotype and glycolytic capacity of Mek1/2 -deficient macrophages. Moreover, trametinib, an Food and Drug Administration-approved MEK1/2 inhibitor, ameliorated chronic cardiac allograft rejection.
Conclusions: These findings suggest that the MEK1/2-PKM2 pathway is essential for immunometabolic reprogramming of proinflammatory AIMs, implying that it may be a promising therapeutic target in clinical heart transplantation.
Competing Interests: The authors declare no conflicts of interest.
(Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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المشرفين على المادة: EC 2.7.1.40 (Pkm protein, mouse)
EC 2.7.12.2 (MAP Kinase Kinase 2)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EC 2.7.12.2 (Map2k1 protein, mouse)
0 (Thyroid Hormone-Binding Proteins)
EC 2.7.12.2 (Map2k2 protein, mouse)
0 (Membrane Proteins)
0 (Carrier Proteins)
EC 2.7.1.40 (Pyruvate Kinase)
تواريخ الأحداث: Date Created: 20240119 Date Completed: 20240425 Latest Revision: 20240426
رمز التحديث: 20240426
مُعرف محوري في PubMed: PMC11042528
DOI: 10.1097/TP.0000000000004899
PMID: 38238904
قاعدة البيانات: MEDLINE
الوصف
تدمد:1534-6080
DOI:10.1097/TP.0000000000004899