TY - JOUR
T1 - Targeting fatty acid β-oxidation impairs monocyte differentiation and prolongs heart allograft survival
AU - Zhu, Yuehui
AU - Dun, Hao
AU - Ye, Li
AU - Terada, Yuriko
AU - Shriver, Leah P.
AU - Patti, Gary J.
AU - Kreisel, Daniel
AU - Gelman, Andrew E.
AU - Wong, Brian W.
N1 - Funding Information:
This work was supported by a grant from the American Society of Transplantation Research Network (to BWW) and by the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation (to BWW). This work was also supported by grants from the NIH (1P01AI116501, to DK and AEG; R01HL094601, to DK; R01HL151078, to DK, R01HL094601, to AEG), a Veterans Administration Merit Review grant (1I01BX002730, to DK), and The Foundation for Barnes-Jewish Hospital (to DK). This work was also supported by the Washington University Institute of Clinical and Translational Sciences, which is, in part, supported by the NIH/National Center for Advancing Translational Sciences Clinical and Translational Science Award grant UL1 TR002345. We acknowledge the Digestive Disease Research Core Center for assistance with histology, the Bursky Center for Human Immunology & Immunotherapy Programs Core Laboratory for assistance with ELIS-POT assays, and the Flow Cytometry & Fluorescence Activated Cell Sorting Core in the Department of Pathology & Immunology and the Siteman Flow Cytometry Core at the Washington University School of Medicine for assistance with flow cytometry.
Publisher Copyright:
Copyright: © 2022, Zhu et al.
PY - 2022/4/8
Y1 - 2022/4/8
N2 - 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 Ccr2deficient 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.
AB - 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 Ccr2deficient 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.
UR - http://www.scopus.com/inward/record.url?scp=85128246498&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.151596
DO - 10.1172/jci.insight.151596
M3 - Article
C2 - 35239515
AN - SCOPUS:85128246498
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 7
M1 - e151596
ER -