Abstract
Fractalkine (FKN), also known as chemokine (C-X3-C motif) ligand 1, constitutes an intriguing chemokine with a documented role in the development of numerous inflammatory diseases including autoimmune disease. Specifically, it has been reported that FKN is involved in the disease progression of lupus nephritis (LN). The epithelial-mesenchymal transition (EMT) plays a significant role in the formation of tubulointerstitial lesions (TIL), which are increasingly recognized as a hallmark of tissue fibrogenesis after injury. However, the correlation between FKN and EMT or TIL in LN has not been determined. To investigate the potential role of FKN in EMT and TIL, MRL lymphoproliferation (MRL/lpr) strain mice were treated with an anti-FKN antibody, recombinant-FKN chemokine domain, or isotype antibody. Our results revealed that treatment with the anti-FKN antibody improved EMT, TIL, and renal function in MRL/lpr mice, along with inhibiting activation of the Wnt/β-catenin signaling pathway. In contrast, administration of the recombinant-FKN chemokine domain had the opposite effect. Furthermore, to further explore the roles of FKN in EMT, we assessed the levels of EMT markers in FKN-depleted or overexpressing human proximal tubule epithelial HK-2 cells. Our results provide the first evidence that the E-cadherin level was upregulated, whereas α-SMA and vimentin expression was downregulated in FKN-depleted HK-2 cells. In contrast, overexpression of FKN in HK-2 cells enhanced EMT. In addition, inhibition of the Wnt/β-catenin pathway by XAV939 negated the effect of FKN overexpression, whereas activation of the Wnt/β-catenin pathway by Ang II impaired the effect of the FKN knockout on EMT in HK-2 cells. Together, our data indicate that FKN plays essential roles in the EMT progression and development of TIL in MRL/lpr mice, most likely through activation of the Wnt/β-catenin signaling pathway.
Highlights
Lupus nephritis (LN) constitutes one of the most important complications of systemic lupus erythematosis (SLE), which is a multisystem autoimmune disease characterized by the deposition of immune complexes [1, 2]
Research has suggested that lupus nephritis (LN) is more highly linked to tubulointerstitial lesions (TIL) than to glomerular fibrosis, and that tubular proteinuria may occur in LN prior to any other marker, such as microalbumunuria [8], suggesting that tubular damage plays a significant role in the progression of LN [9, 10]
C, recombinant-FKN stimulated the activation of Nuclear factorκB (NF-κB) and upregulated the expression of TGFβ, CCL22, and F4/80, anti-FKN antibody suppressed the activation of NF-κB and downregulated the expression of TGFβ, CCL22, and F4/80 in MRL lymphoproliferation (MRL/lpr) mice renal. These results suggested that the Wnt/βcatenin pathway accompanied by NF-κB and TGFβ pathway is involved in the FKN-mediated epithelial-mesenchymal transition (EMT) and TIL, which is due to the accumulation of macrophages and macrophages-derived factors in the murine model of LN
Summary
Lupus nephritis (LN) constitutes one of the most important complications of systemic lupus erythematosis (SLE), which is a multisystem autoimmune disease characterized by the deposition of immune complexes [1, 2]. Upwards of 60% of patients with SLE develop LN [3, 4], of which renal fibrosis is the main feature. Growing evidence demonstrates that the response of renal tubule lesions plays a vital role in the progression of renal disease [7]. Research has suggested that LN is more highly linked to tubulointerstitial lesions (TIL) than to glomerular fibrosis, and that tubular proteinuria may occur in LN prior to any other marker, such as microalbumunuria [8], suggesting that tubular damage plays a significant role in the progression of LN [9, 10]. TIL is present in a higher proportion of patients with SLE; it has been reported that TIL may serve as a single causative risk factor underlying LN pathological changes [13]. It would be valuable to explore the pathological process of TIL in LN
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