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  • Nogo-66 (1-40) br Hypothesis on DDR protective mode of actio


    Hypothesis on DDR1 protective mode of action The documented protective role of DDR1 is quite impressive, demonstrated using different preclinical models (immunologic [46,54,58], obstructive [45], and hypertensive [50]) with different intervention paradigms: genetic ablation [45,50,58,72], silencing [46] as well as with rather unselective [55] and highly selective pharmacological modulation [19] of the target using a DDR1 tyrosine kinase inhibitor, in different organs. Despite this impressive quantity of evidence, the mechanism by which protection is achieved remains obscure. We attempt below to summarize the view of the co-authors regarding DDR1 protective MoA. Our hypotheses and speculations are based on collated scientific evidence coming from independent studies, within and outside the fibrosis research domain. First, from a literature survey, DDR1 seems to have a key role in fibrosis only in certain organs, namely in kidney and lung. DDR1's role in skin fibrosis as well as in liver and heart fibrosis is not well understood and studies using well characterized probes are needed. The lack of understanding is perhaps surprising as fibrotic processes are thought to be well conserved across organs and organisms, shaped by the selective pressure exerted by Darwinian evolution. Interestingly, this notion of different susceptibility of organs to fibrosis has been recently experimentally-induced by transgenic overexpression of c-Jun transcription factor in fibroblasts by Wernig et al. [73]. Though advocating for a unifying mechanism for fibrosis, authors clearly state that: “systemically c-Jun–induced mice revealed severe fibrosis of bone marrow and the skin, whereas other organs were much less affected, such as the lung that showed only a mild interstitial fibrosis” [73]. The predominant role of DDR1 in lung and kidney might therefore be explained by differences in organ susceptibility to fibrosis, although we can't rule out bias by research groups focusing on only those organs. Certainly the role of DDR1 in different organ fibrosis is not in relation to the level of expression. DDR1 and DDR2 Nogo-66 (1-40) profile appear to be very similar in kidney and skin yet very different between kidney and lung, even though the latter are the two organs where DDR1 deletion provides organ protection. Another interesting element is that DDR1 does not have functional redundancy with the closely related DDR2 receptor. DDR2 is in fact expressed mainly in cells of mesenchymal origin with a striking phenotypic difference between the relatively subtle phenotype of the DDR1 deficient mouse [15] versus the overt phenotype of the DDR2−/− [74,75] mouse. DDR2 seems also to play a very different role in fibrosis, genetic ablation of DDR2 in experimentally-induced liver fibrosis in fact worsens the course of the fibrotic process [67] whereas ablation of DDR1 in both kidney [45,46,50,72,76] and lung [58] improves it. In our opinion, though closely related in terms of protein structure, DDR1 and DDR2 seem to be functionally very distinct and control different biological processes with potentially opposite roles in the onset and progression of the fibrotic lesion, a topic that would deserve careful study. DDR1 is uniquely expressed in epithelial cells, and so its protection mechanism is therefore likely mediated by paracrine modulation exerted by epithelial cells, under the control of collagen, on the surrounding fibroblasts. The modulation of this paracrine dialogue seems to occur very differently in normal or injured tissues. In normal homeostatic conditions, absence of DDR1 does not appear to be beneficial resulting in modulation of the resident quiescent stromal component toward an activated myofibroblast phenotype [15]. Similarly, loss of cell-matrix communication in DDR1-deficient podocytes appears to result in excess synthesis of basement membrane proteins leading to disturbed anchorage of foot processes and disruption of the slit diaphragm. Those structural changes induce middle-to high-molecular weight proteinuria [49]. On the other hand, in the pathological context, in lung [58] and kidney [19,45,46,50,54] fibrosis models, DDR1 gene deletion has a clear protective effect reducing inflammation both acute [77] and chronic [19,45,46,50,54] experimental models: reducing myofibroblast activation and ECM accumulation resulting in protection and/or preservation of organ function.