Abstract
The role of fibroblasts in tissue fibrosis has been extensively studied. Activated fibroblasts, namely myofibroblasts, produce pathological extracellular matrix. CD248, a type I transmembrane glycoprotein, is expressed in fibroblasts after birth. In human chronic kidney disease, upregulated CD248 in myofibroblasts is linked to poor renal survival. In this study, we demonstrated a novel interaction between CD248 and macrophages to be a key step in mediating tissue fibrosis. CD248 was upregulated in myofibroblasts in murine models of renal and peritoneal fibrosis. Cd248 knockout (Cd248–/–) could attenuate both renal and peritoneal fibrosis. By parabiosis of GFP reporter mice and Cd248–/– mice, we showed that attenuation of renal fibrosis was associated with a decrease of macrophage infiltration in Cd248–/– mice. Moreover, decrease of chemokine (C–C motif) ligand 17 and Ccl22 was found in macrophages isolated from the fibrotic kidneys of Cd248–/– mice. Because galectin-3-deficient macrophages showed decreased Ccl17 and Ccl22 in fibrotic kidneys, we further demonstrated that CD248 interacted specifically with galectin-3 of macrophages who then expressed CCL17 to activate collagen production in myofibroblasts. Mice with DNA vaccination targeting CD248 showed decreased fibrosis. We thus propose that CD248 targeting should be studied in the clinical tissue fibrosis setting.
Highlights
The role of fibroblasts in tissue fibrosis has been extensively studied
By fluorescence-activated cell sorting (FACS) from Col1a1-GFPTg mice, pericytes and myofibroblasts were isolated from the control kidney and ureteral obstruction (UUO) fibrotic kidney, respectively
It may be that a combination of signals from epithelial cells, endothelial cells, myofibroblasts, and perhaps other inflammatory cells trigger phenotype switching in recruited m acrophages[14,17,18,30]
Summary
The role of fibroblasts in tissue fibrosis has been extensively studied. Activated fibroblasts, namely myofibroblasts, produce pathological extracellular matrix. Many studies, including ours, have identified pericytes and perivascular fibroblasts as the major progenitor cells of scar-producing myofibroblasts during renal fibrosis[4,5,6,7,8,9,10,11,12]. In addition to being the master regulators of immune cells involved in tissue destruction and remodeling in sterile inflammatory organs, macrophages produce a broad range of paracrine-signaling cytokines, thereby stimulating neighboring scar-producing myofibroblasts to proliferate and synthesize pathological extracellular matrix proteins, such as collagen I4,14,17–20. In murine progressive fibrosis models, including those for the kidney, liver, lung, skin and peritoneum, the examination of monocyte trafficking has shown that circulating Ly6Chigh pro-inflammatory monocytes are selectively recruited to injured tissues and differentiate into an Ly6Clow pro-fibrotic population[14,18,21,22,23,24]. We here demonstrated the role of CD248 in activation of myofibroblasts and pro-fibrotic phenotype switch of macrophages during progressive fibrosis
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