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  • DDR distribution in healthy fibrotic and inflamed

    2021-01-12

    DDR1 distribution in healthy, fibrotic and inflamed tissues Whereas we can easily mine publicly available databases to infer DDR1 expression profile in different tissues (as reported in Fig. 1), fine comprehension of DDR1 biology has been hampered by the absence of a commercially available specific anti-human DDR1 antibody. For that reason, co-authors of the present review (S.M., M.P.) have devoted quite some time to clone and characterize (using both DDR1 and DDR2 overexpressing cell lines as well as naturally overexpressing cancer cell lines) [19] a highly selective anti-human DDR1. The coherent picture emerging for the expression of DDR1 in the skin, liver, kidney and lung is summarized in Fig. 2. In normal skin, DDR1 is expressed in keratinocytes and in epithelial salubrinal of glands whereas dermal fibroblasts do not express DDR1. In hypertrophic scars, DDR1 retains the same expression patterns in epithelial cells whereas no DDR1 was observed in myofibroblasts or in vascular smooth muscle cells. In normal liver, DDR1 is expressed in bile duct epithelial cells and at the periphery of hepatocytes, especially at the portal parenchymal interface. Portal fibroblasts do not express DDR1. In cholangiocarcinoma, DDR1 is expressed in proliferating tumoral epithelial cells but not in myofibroblasts. In normal kidney, DDR1 is expressed in the distal tubular cells and in the parietal epithelial cells of the Bowman capsule. In chronic kidney disease such as diabetic nephropathy, DDR1 retains the same expression patterns in tubular epithelial cells whereas no DDR1 expression is observed in myofibroblasts. In normal lung, DDR1 is expressed in bronchiolar epithelial cells as well as in type 1 and 2 alveolar pneumocytes. In IPF, DDR1 retains the same expression patterns in bronchiolar and alveolar epithelia whereas no positivity is observed in myofibroblasts. Further analysis of DDR1 expression using the same anti-human DDR1 antibody [19] was performed in normal human vessels (renal artery) as well as in two types of vascular disease: atherosclerosis and giant-cell arteritis (or temporal arteritis, an inflammatory condition of the blood vessels characterized by intimal hyperplasia and medial granulomatous inflammation with elastic lamina fragmentation with a predominant CD4+ cell infiltrate) (Fig. 3). We could not detect any DDR1 staining in either the media of the normal vessels or in both vascular diseases. In addition, no DDR1 signal could be detected in inflammatory cells (macrophages, giant cells and lymphocytes) present in both atherosclerosis and giant-cell arteritis. Finally, to shed further light on the expression of DDR1 in inflammatory cells, we analyzed three different types of human renal inflammatory diseases: acute T cell-mediated (cellular) rejection of the renal allograft, drug-induced tubulo-interstitial nephritis and BK virus nephritis in the renal transplant patient (Fig. 3). Inflammatory cells of cellular rejection are predominantly lymphocytes and macrophages and those of drug-induced and BK virus nephrites lymphocytes, macrophages and plasma cells. No DDR1 staining could be detected in lymphocytes and macrophages, as observed in acute T cell-mediated rejection – substantially confirming our prior observation in vascular diseases. However, DDR1 positivity was clearly detected in plasma cells of both drug-induced and viral nephrites, with stronger staining in drug-induced nephritis biopsies. This difference in intensity of the DDR1 plasma cell staining could be explained by a higher degree of plasma cell infiltration typical of that condition. The above results, produced with a specific and selective anti-human DDR1 antibody, indicate that expression of DDR1 is exclusively limited to epithelial cells in both normal tissues as well as in fibrotic lesions in the skin, liver, kidney and lung and that DDR1 is expressed in tissue infiltrating plasma cells.
    Insights from the skin, fibrogenesis and experimentally-induced wound healing DDR1 mouse models