Macrophage/monocyte-specific deletion of Ras homolog gene family member A (RhoA) downregulates fractalkine receptor and inhibits chronic rejection of mouse cardiac allografts.
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)/chemokine (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 RhoAflox/flox(no Cre) and heterozygous Lyz2Cre+/-RhoAflox/floxrecipients 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.
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Yianzhu
Y
Liu
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas.
Wenhao
W
Chen
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas; The Organ Transplant Center, The First Affiliated Hospital, Su Yat-sen University and Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Gungzhou, China.
Chenglin
C
Wu
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas.
Laurie J
LJ
Minze
CNRS UMR 6290, Institute of Genetics and Development of Rennes, Cell Cycle Group, IFR 140 GFAS, France; University of Rennes 1, Faculty of medicine, Rennes, France; Department of Regenerative Medicine, Military Institute of Hygiene and Epidemiology (WIHE), Warsaw, Poland.
Jacek Z
JZ
Kubiak
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas.
Xian C
XC
Li
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas. Electronic address: mkloc@houstonmethodist.org.
Malgorzata
M
Kloc
The Houston Methodist Research Institute, Houston, Texas; Department of Surgery, The Houston Methodist Hospital, Houston, Texas; University of Rennes 1, Faculty of medicine, Rennes, France; The Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, Texas.
Rafik M
RM
Ghobrial
D064591:Allografts; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D015536:Down-Regulation; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics* / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000379:methods; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology; D011897:Random Allocation; D023062:Receptors, Interleukin-8A / Q000235:genetics*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000235:genetics*; D020742:rhoA GTP-Binding Protein
D023062:Receptors, Interleukin-8A; C526380:RhoA protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
CX3CR1; RhoA; actin; chronic rejection; fractalkine; macrophage
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