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Targeting fibroblast CD248 attenuates CCL17-expressing macrophages and tissue fibrosis
Chen-Hsueh Pai1, Shu-Rung Lin2,3, Chia-Hao Liu4
1Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
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.
Insights
CD248 protein interaction with macrophage galectin-3 drives tissue fibrosis by increasing chemokines. Targeting CD248 reduced fibrosis, suggesting a potential therapeutic strategy for fibrotic diseases.
Area of Science:
- Fibrosis research
- Immunology
- Molecular biology
Background:
- Fibroblasts, specifically myofibroblasts, are key players in tissue fibrosis through pathological extracellular matrix production.
- CD248, a transmembrane glycoprotein in fibroblasts, is upregulated in chronic kidney disease and linked to poor renal survival.
Purpose of the Study:
- To investigate the novel interaction between CD248 and macrophages in mediating tissue fibrosis.
- To explore the therapeutic potential of targeting CD248 in fibrotic conditions.
Main Methods:
- Utilized murine models of renal and peritoneal fibrosis.
- Employed Cd248 knockout (Cd248-/-) and parabiosis experiments with GFP reporter mice.
- Analyzed chemokine expression (CCL17, CCL22) in macrophages and investigated CD248 interaction with galectin-3.
- Assessed fibrosis reduction via DNA vaccination targeting CD248.
Main Results:
- Cd248 knockout attenuated renal and peritoneal fibrosis, correlating with decreased macrophage infiltration.
- Macrophages from Cd248-/- mice showed reduced expression of CCL17 and CCL22.
- CD248 was found to interact with macrophage galectin-3, leading to CCL17 expression and subsequent collagen production by myofibroblasts.
- DNA vaccination targeting CD248 significantly decreased fibrosis.
Conclusions:
- The interaction between CD248 on myofibroblasts and galectin-3 on macrophages is a critical mechanism in driving tissue fibrosis.
- Targeting CD248 presents a promising therapeutic avenue for managing fibrotic diseases.
