Depletion of Fractalkine Ameliorates Renal Injury and Treg Cell Apoptosis via the p38MAPK Pathway in Lupus-Prone Mice

Abstract Background Fractalkine is a chemokine with several roles, including chemotaxis, adhesion, and immune damage. It participates in cell inflammation and apoptosis and responds to the pathogenesis of autoimmune diseases. On the other hand, Treg cells are involved in autoimmune diseases. This study aimed to explore the regulatory mechanism of Fractalkine in renal injury and Treg apoptosis via the p38MAPK signalling pathway in lupus-prone mice. Methods Lupus was induced in BALB/c female mice by injection of pristane. Then, CD4+ CD5+ Treg cells were isolated from the spleen of lupus mice. To deplete Fractalkine, first, mice received an injection of anti-Fractalkine antibody. Later, the transfection of Treg cells with Fractalkine siRNA was conducted. Lupus mice and Treg cells were treated with the p38MAPK inhibitor SB203580 and/or activator U-46619, respectively. The levels of urine protein, serum urea nitrogen, creatinine, and autoantibodies were measured from mouse samples, and renal histopathological features were analysed. The expression of Fractalkine, p-p38, Foxp3, IL-6, and IL-17 in the mouse kidney and Treg cells was detected. The levels of apoptosis and key apoptotic factors: Bax, Bcl-2, and Cyt-c in Treg cells were analysed. Results The expression of Fractalkine, p-p38, IL-6, and IL-17 increased; meanwhile, that of Foxp3 decreased in the kidneys of mice with lupus. The depletion of Fractalkine and p38MAPK levels ameliorated proteinuria and renal functions and significantly reduced serum autoantibodies, renal Fractalkine, p-p38, IL-6, and IL-17 levels, while increasing renal Foxp3 concentration in lupus mice. The effects of Fractalkine knockdown (KD) and p38MAPK inhibitor on Treg cells, derived from lupus mice, were consistent with those observed in the kidneys. In addition, Fractalkine KD reduced cell apoptosis and suppressed the activation of p38MAPK signalling in Treg cells, derived from lupus mice. Meanwhile, the p38MAPK activator U-46619 had the opposite effect. Conclusion Together, our data indicated that Fractalkine promoted the nephritis progression in lupus mice, most likely through the regulation of Treg cell apoptosis and activation of the p38MAPK signalling pathway. It suggested that targeting Fractalkine is a potential therapeutic strategy for treating LN.