Journal
JOURNAL OF HEART AND LUNG TRANSPLANTATION
Volume 36, Issue 3, Pages 340-354Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.healun.2016.08.011
Keywords
RhoA; chronic rejection; fractalkine; CX3CR1; macrophage; actin
Funding
- William Stamps Farish Fund
- Donald D. Hammill Foundation
- NIH [R01AI080779]
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BACKGROUND: The cellular and molecular mechanisms of chronic rejection of transplanted organs remain obscure; however, macrophages are known to play a critical role in the injury and repair of allografts. Among multiple factors influencing macrophage infiltration to allografts, the fractalkine chemokine (C-X3-C motif) ligand 1(CX3CL1)/chemoldne (C-X3-C motif) receptor 1 (CX3CR1) signaling pathway and actin cytoskeleton, which is regulated by a small guanosine-5'-triphosphatase Ras homolog gene family member A (RhoA), are of the utmost importance. To define the role of macrophage/RhoA pathway involvement in chronic rejection, we generated mice with monocyte/macrophage-specific deletion of RhoA. METHODS: Hearts from BALB/c (H-2d) donors were transplanted into RhoA(flox/flox) (no Cre) and heterozygous Lyz2(cre+/-)RhoA(flox/flox) recipients treated with cytotoxic T-lymphocyte associated protein 4 immunoglobulin to inhibit early T-cell response. Allografts were assessed for chronic rejection and monocyte/macrophage functions. RESULTS: The deletion of RhoA inhibited macrophage infiltration, neointimal hyperplasia of vasculature, and abrogated chronic rejection of the allografts. The RhoA deletion downregulated G protein-coupled fractalkine receptor CX3CR1, which activates the RhoA pathway and controls monocyte/macrophage trafficking into the vascular endothelium. This in turn promotes, through overproliferation and differentiation of smooth muscle cells in the arterial walls, neointimal hyperplasia. CONCLUSIONS: Our finding of codependence of chronic rejection on monocyte/macrophage CX3CR1/CX3CL1 and RhoA signaling pathways may lead to the development of novel anti-chronic rejection therapies. (C) 2017 International Society for Heart and Lung Transplantation,. All rights reserved.
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