br DDR in atherosclerosis and vascular disease
DDR1 in atherosclerosis and vascular disease The Canadian group of Bendeck, explored the role of DDR1 in repair following arterial injury in rats . DDR1 protein levels, assessed via Western blots prepared from arterial extracts taken at various times after injury, showed DDR1 protein dramatically increased in the injured rat carotid 1 day after balloon injury and was elevated again 14 days after injury. Immunostaining of injured rat carotid cross-sections with an anti-human DDR1 Ab showed DDR1 expression in smooth muscle cells (SMCs) immediately subjacent to the lumen 2 days after injury. There was intense staining of the migrating neointimal SMCs 4 days after injury, which persisted throughout the thickness of the intima at 14 days. We raise to the readers' attention the very poor quality of the immunohistochemistry of this paper (specifically Fig. 2 ) generated using a non-validated rabbit polyclonal antibody (Santa Cruz Biotechnology, cyclic amp function 894–913) directed against the human DDR1 carboxy-terminus. As mentioned above, co-authors of this review, using a highly selective anti-human DDR1 antibody , validated on specific cancer cells and on DDR1 and DDR2 recombinant cells, were never able to detect expression of DDR1 in fibroblasts or in myofibroblasts (see Fig. 2) involved in normal or pathological (excessive) skin repair processes. The Bendeck team, in the same paper, also observed dramatic attenuation of intimal thickening after vascular injury in DDR1-null mice compared with wild-type controls. Interestingly, the authors, using picrosirius red stain and polarized-light microscopy to visualize collagen birefringence, noted a substantial decrease in the deposition of collagen fibrils in the intima of the DDR1-null mice compared with wild-type controls . However, the role of DDR1 seems more complex insofar as the same team observed that DDR1 deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice . More recently, it was shown that DDR1 expression on resident vessel wall smooth muscle cells limits proliferation, migration and matrix accumulation during atherogenesis . Overall, these studies suggest that DDR1 contributes to atherosclerosis by increasing the number of macrophages and by decreasing extracellular matrix deposition. As already mentioned above, it is the opinion of the co-authors of this review that DDR1 is not expressed in either macrophages (see Fig. 3), or normal SMCs but it might be expressed in vascular-activated SMCs undergoing a phenotypic switch from contractile to synthetic as they proliferate and migrate into a lesion, elaborating a collagen-rich matrix. This notion seems to be in agreement with further work by Bendeck's lab investigating DDR1 role in vascular SMCs during atherosclerosis and following vascular injury . Similar evidence for absence of DDR1 expression in stable SMCs has been shown by other authors .
DDR1 expression in inflammatory cells Inflammatory cells play a key role in the initiation and progression of the fibrotic lesion . In the published literature very few groups have studied the expression and functions of DDR1 in inflammatory cells. This picture is further complicated by a series of papers, describing specifically the role of DDR1 in CD14-positive cells , in monocyte-derived dendritic cells  and macrophages  retracted respectively in J. Immunol 2008 , in J. Immunol, 2010  and in FASEB . Apart from this group, other authors indicated a role for DDR1 in microglia  though again that paper traces back to previous work by the same authors showing that DDR1 mediates collagen-induced macrophage activation  using an antibody described by Matsuyama and Yoshimura , the same authors that had DDR1 papers retracted by the lead principal investigator, Dr. Yoshimura. Other evidence in the literature for a role of DDR1 in macrophages (summarized in a review of DDR1 role in renal diseases ) has been reported, using an anti-DDR1 from Santa Cruz Biotechnology (clone C-20), by the group of Christos Chantziantoniou in Paris in unilateral ureteral obstruction , an accelerated model of renal fibrosis. The same group investigated in a second paper DDR1 in T-cells, though in this case the expression of DDR1 in inflammatory cells is not clearly indicated and, as noticed by the same authors, there was striking contrasting evidence from in vitro and in vivo settings, with DDR1 supposedly having a role on T-cell migration in vitro but absent expression in T-lymphocyes in vivo . As we previously mentioned in the dedicated paragraph (and further exposed in Fig. 3), the co-authors of this review are inclined to consider DDR1 normally not expressed in inflammatory cells except plasma cells.