Background The cellular and molecular mechanisms of chronic rejection of transplanted organs remain obscure. It is known however that macrophages play a critical role in the injury and repair of allografts. Among multiple factors influencing macrophage infiltration to allografts, the fractalkine CX3CL1/ CX3CR1 signaling pathway and actin cytoskeleton, which is regulated by a small GTPase 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/flox recipients treated with CTLA4-Ig 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 down-regulated G protein-coupled fractalkine receptor CX3CR1, which activates RhoA pathway and controls monocyte/macrophage trafficking into the vascular endothelium. This in turn promotes, through over-proliferation and differentiation of smooth muscle cells in the arterial walls, neointimal hyperplasia. Conclusions Our finding of co-dependence of chronic rejection on monocyte/macrophage CX3CR1/CX3CL1 and RhoA signaling pathways may lead to development of novel anti-chronic rejection therapies.

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