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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.

Titel:	MEK1/2-PKM2 Pathway Modulates the Immunometabolic Reprogramming of Proinflammatory Allograft-infiltrating Macrophages During Heart Transplant Rejection.
Autor/in / Beteiligte Person:	Chen, Z ; Li, Y ; Niu, Y ; Zhang, X ; Yu, J ; Cui, J ; Ran, S ; Wang, S ; Ye, W ; Xia, J ; Wu, J
Zeitschrift:	Transplantation, Jg. 108 (2024-05-01), Heft 5, S. 1127-1141
Veröffentlichung:	Hagerstown, MD : Lippincott Williams & Wilkins ; <i>Original Publication</i>: Baltimore, Williams & Wilkins., 2024
Medientyp:	academicJournal
ISSN:	1534-6080 (electronic)
DOI:	10.1097/TP.0000000000004899
Schlagwort:	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 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
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Transplantation] 2024 May 01; Vol. 108 (5), pp. 1127-1141. <i>Date of Electronic Publication: </i>2024 Jan 19. MeSH Terms: 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 References: Nature. 2023 Sep;621(7980):830-839. (PMID: 37674079) ; Immunity. 2017 Dec 19;47(6):1114-1128.e6. (PMID: 29221730) ; J Clin Invest. 2017 Jun 30;127(7):2473-2481. (PMID: 28628037) ; Transplantation. 2022 Feb 1;106(2):257-267. (PMID: 33908380) ; J Biol Chem. 2017 Aug 18;292(33):13615-13634. (PMID: 28679535) ; Oncogene. 2019 Mar;38(13):2223-2240. (PMID: 30487597) ; Am J Transplant. 2016 Sep;16(9):2563-73. (PMID: 27575724) ; Basic Res Cardiol. 2021 Dec 6;116(1):64. (PMID: 34870762) ; J Heart Lung Transplant. 2015 Oct;34(10):1264-77. (PMID: 26454740) ; Science. 2016 Apr 22;352(6284):aaf1098. (PMID: 27102489) ; Annu Rev Pathol. 2009;4:19-47. (PMID: 18717641) ; Transplantation. 2017 Jan;101(1):45-55. (PMID: 27547865) ; Am J Transplant. 2018 Mar;18(3):604-616. (PMID: 29044999) ; N Engl J Med. 2012 Jul 12;367(2):107-14. (PMID: 22663011) ; Am J Transplant. 2021 Oct;21(10):3280-3295. (PMID: 33764625) ; Am J Transplant. 2015 Sep;15(9):2364-77. (PMID: 25943210) ; Immunity. 2018 Nov 20;49(5):819-828.e6. (PMID: 30413362) ; Cell Mol Immunol. 2021 Apr;18(4):1079-1081. (PMID: 32801366) ; Immunity. 2015 Mar 17;42(3):419-30. (PMID: 25786174) ; Annu Rev Immunol. 2021 Apr 26;39:667-693. (PMID: 33637018) ; J Clin Invest. 2017 Jun 30;127(7):2464-2472. (PMID: 28530643) ; Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15160-15171. (PMID: 32541026) ; Immunity. 2015 Mar 17;42(3):393-4. (PMID: 25786167) ; Crit Care Med. 2016 Aug;44(8):e711-20. (PMID: 27031380) ; Immunity. 2016 Oct 18;45(4):817-830. (PMID: 27760338) ; J Exp Med. 2016 Mar 7;213(3):337-54. (PMID: 26926996) ; J Clin Invest. 2020 Oct 1;130(10):5397-5412. (PMID: 32644975) ; Immunity. 2014 Jul 17;41(1):14-20. (PMID: 25035950) ; Nat Cell Biol. 2012 Dec;14(12):1295-304. (PMID: 23178880) ; Nat Rev Immunol. 2016 Sep;16(9):553-65. (PMID: 27396447) ; Biomark Res. 2021 Jan 6;9(1):1. (PMID: 33407885) ; Transplant Direct. 2020 Aug 12;6(9):e591. (PMID: 32851124) ; Cell Metab. 2015 Jan 6;21(1):65-80. (PMID: 25565206) ; Lancet Oncol. 2016 Jul;17(7):984-993. (PMID: 27283860) ; Nat Commun. 2020 Apr 14;11(1):1769. (PMID: 32286295) ; Nature. 2013 Jan 17;493(7432):346-55. (PMID: 23325217) ; Circ Res. 2022 Apr 29;130(9):1289-1305. (PMID: 35400205) ; N Engl J Med. 2007 Sep 13;357(11):1121-35. (PMID: 17855673) ; Front Immunol. 2018 Feb 19;9:270. (PMID: 29520272) ; J Exp Med. 2016 Jan 11;213(1):15-23. (PMID: 26694970) ; Am J Transplant. 2007 Dec;7(12):2675-82. (PMID: 17924996) ; Immunity. 2016 Mar 15;44(3):450-462. (PMID: 26982353) ; Theranostics. 2022 Aug 29;12(14):6242-6257. (PMID: 36168621) ; Cell Immunol. 2020 Mar;349:104064. (PMID: 32061375) ; Int J Chron Obstruct Pulmon Dis. 2019 Nov 26;14:2611-2624. (PMID: 32063702) ; Circ Res. 2020 Sep 25;127(8):974-993. (PMID: 32689904) Substance Nomenclature: 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) Entry Date(s): Date Created: 20240119 Date Completed: 20240425 Latest Revision: 20240426 Update Code: 20240426 PubMed Central ID: PMC11042528

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