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 naïve 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

Venturini M.;
2021-01-01

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 naïve 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.
2021
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
Usuelli, V.; Ben Nasr, M.; D'Addio, F.; Liu, K.; Vergani, A.; El Essawy, B.; Yang, J.; Assi, E.; Uehara, M.; Rossi, C.; Solini, A.; Capobianco, A.; Rigamonti, E.; Potena, L.; Venturini, M.; Sabatino, M.; Bottarelli, L.; Ammirati, E.; Frigerio, M.; Castillo-Leon, E.; Maestroni, A.; Azzoni, C.; Loretelli, C.; Joe Seelam, A.; Tai, A. K.; Pastore, I.; Becchi, G.; Corradi, D.; Visner, G. A.; Zuccotti, G. V.; Chau, N. B.; Abdi, R.; Pezzolesi, M. G.; Fiorina, P.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2114076
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