Targeting fatty acid β-oxidation impairs monocyte differentiation and prolongs heart allograft survival.

Yuehui Zhu,Leah P Shriver,Hao Dun,Yuriko Terada,Andrew E Gelman,Brian W Wong,Daniel Kreisel,Gary J Patti,Li Ye

doi:10.1172/jci.insight.151596

Abstract

Monocytes play an important role in the regulation of alloimmune responses after heart transplantation (HTx). Recent studies have highlighted the importance of immunometabolism in the differentiation and function of myeloid cells. While the importance of glucose metabolism in monocyte differentiation and function has been reported, a role for fatty acid β-oxidation (FAO) has not been explored. Heterotopic HTx was performed using hearts from BALB/c donor mice implanted into C57BL/6 recipient mice and treated with etomoxir (eto), an irreversible inhibitor of carnitine palmitoyltransferase 1 (Cpt1), a rate-limiting step of FAO, or vehicle control. FAO inhibition prolonged HTx survival, reduced early T cell infiltration/activation, and reduced DC and macrophage infiltration to heart allografts of eto-treated recipients. ELISPOT demonstrated that splenocytes from eto-treated HTx recipients were less reactive to activated donor antigen-presenting cells. FAO inhibition reduced monocyte-to-DC and monocyte-to-macrophage differentiation in vitro and in vivo. FAO inhibition did not alter the survival of heart allografts when transplanted into Ccr2-deficient recipients, suggesting that the effects of FAO inhibition were dependent on monocyte mobilization. Finally, we confirmed the importance of FAO on monocyte differentiation in vivo using conditional deletion of Cpt1a. Our findings demonstrate that targeting FAO attenuates alloimmunity after HTx, in part through impairing monocyte differentiation.

Highlights

Heart transplantation (HTx) is the preferred treatment for numerous patients with end-stage heart failure; it provides a median survival of approximately 12 years and a significant improvement in quality of life [1, 2]
Our investigation of central carbon flux in monocytes showed a significant increase in fatty acid β-oxidation (FAO) flux after 48-hour incubation following either granulocyte macrophage colony-stimulating factor (GM-CSF) + IL4 or macrophage colony-stimulating factor (M-CSF) stimulation, which was sharply inhibited by pharmacological inhibition of FAO (Figure 4C)
We demonstrate that pharmacological inhibition of FAO significantly prolongs heart allograft survival

Summary

Introduction

Heart transplantation (HTx) is the preferred treatment for numerous patients with end-stage heart failure; it provides a median survival of approximately 12 years and a significant improvement in quality of life [1, 2]. Calcineurin inhibitors (FK506; cyclosporine) remain the primary immunosuppressive agent, despite the advent of newer immunosuppressants, such as mTOR inhibitors (rapamycin [sirolimus]; everolimus) or costimulation blockers (anti–CTLA4-immunoglobulin; belatacept). All these immunosuppressive agents (including the adjuvant therapies of corticosteroids and mycophenolic acid) mechanistically target T cell proliferation, and, despite robust suppression of acute T cell responses that have led to dramatic reductions in acute rejection, chronic allograft rejection remains. In acute kidney allograft rejection, monocyte infiltration has been quantitatively associated with renal dysfunction [8], and monocyte-mediated acute renal rejection has been reported after inhibition of T cell infiltration by alemtuzumab [9]. Monocyte-derived DCs have been reported to impair early graft function in islet transplantation [14] and can promote cardiac allograft rejection [15]

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