Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naive macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.

miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy / V. Usuelli, M. Ben Nasr, F. D'Addio, K. Liu, A. Vergani, B. El Essawy, J. Yang, E. Assi, M. Uehara, C. Rossi, A. Solini, A. Capobianco, E. Rigamonti, L. Potena, M. Venturini, M. Sabatino, L. Bottarelli, E. Ammirati, M. Frigerio, E. Castillo-Leon, A. Maestroni, C. Azzoni, C. Loretelli, A.J. Seelam, A.K. Tai, I. Pastore, G. Becchi, D. Corradi, G.A. Visner, G. Vincenzo Zuccotti, B.N. Chau, R. Abdi, M.G. Pezzolesi, P. Fiorina. - In: AMERICAN JOURNAL OF TRANSPLANTATION. - ISSN 1600-6135. - 21:10(2021 Mar 25), pp. 3280-3295. [10.1111/ajt.16581]

miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy

V. Usuelli
Primo
;
M. Ben Nasr;F. D'Addio;E. Assi;E. Rigamonti;A. Maestroni;C. Loretelli;A.J. Seelam;G. Vincenzo Zuccotti;P. Fiorina
Ultimo
2021

Abstract

Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naive macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.
basic (laboratory) research / science; heart (allograft) function / dysfunction; heart transplantation / cardiology; immunobiology; macrophage / monocyte biology: activation; molecular biology: micro RNA; rejection: vascular; translational research / science
Settore MED/13 - Endocrinologia
Settore MED/50 - Scienze Tecniche Mediche Applicate
ott-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/841365
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