Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
Int Immunopharmacol. 2023 Jul;120:110297. doi: 10.1016/j.intimp.2023.110297. Epub 2023 May 17.
Overexpression of Staphylococcus aureus mediated CXCL8/CXCR1 axis is a major cause of sepsis and severe inflammatory diseases. This chemokine acts conjointly with various pro-inflammatory and anti-inflammatory cytokines that govern the severity of inflammation. The effects of different combinations of exogenous cytokines on CXCR1 expression in macrophages remain undetermined. Exogenous cytokine and anti-inflammatory cytokine therapy had been used to modulate CXCL8 and CXCR1 expression in peritoneal macrophages. Male Swiss albino mice were inoculated with live S. aureus (10 cells/ mouse) for the development of infection. Exogenous cytokines (TNF-α, IL-12, IFN-γ and IL-10) were administered intraperitoneally (single or combination) 24 h post S. aureus infection. The mice were sacrificed and peritoneal macrophages were isolated three days post infection. CXCL8, IL-12, IL-10 secretion, ROS generation and the bacterial phagocytic process had been evaluated. Western blot was used to study the expressions of TNFR1, IL-1R, CXCR1 and NF-κB. TNF-α, IL-12 and IFN-γ treatments aggravated CXCL8 and CXCR1 expression in the macrophages of infected mice. TNF-α + IFN-γ treatment was a major inducer of nitric oxide release and mediated maximum bacterial killing. IL-12 + TNF-α treatment was most potent in increasing ROS, CXCL8/CXCR1 expression through increased levels of TNFR1, IL-1R and NF-κB activation. IL-10 reversed the effects of exogenous cytokines but also impaired the bacterial clearance phenomenon in peritoneal lavage. Treatment with IL-12 + TNF-α + IL-10 was most effective in ameliorating oxidative stress, reduced CXCL8 release and expression levels of TNFR1, IL-1R, and NF-κB. Concludingly, IL-12 + TNF-α + IL-10 treatment mitigated CXCL8/CXCR1 expression and inflammatory signalling via downregulation of TNFR1-IL-1R-NF-κB pathway in peritoneal macrophages and inflammatory sequelae during S. aureus infection.
金黄色葡萄球菌过表达介导的 CXCL8/CXCR1 轴是脓毒症和严重炎症性疾病的主要原因。这种趋化因子与各种促炎和抗炎细胞因子共同作用，调节炎症的严重程度。不同组合的外源性细胞因子对巨噬细胞中 CXCR1 表达的影响尚不确定。曾使用外源性细胞因子和抗炎细胞因子疗法来调节腹腔巨噬细胞中 CXCL8 和 CXCR1 的表达。雄性瑞士白化病小鼠用活的金黄色葡萄球菌（10 个细胞/只）接种以诱导感染。在金黄色葡萄球菌感染后 24 小时内，通过腹腔内注射（单一或组合）给予外源性细胞因子（TNF-α、IL-12、IFN-γ 和 IL-10）。感染后 3 天处死小鼠并分离腹腔巨噬细胞。评估 CXCL8、IL-12、IL-10 的分泌、ROS 的产生和细菌吞噬过程。使用 Western blot 研究 TNFR1、IL-1R、CXCR1 和 NF-κB 的表达。TNF-α、IL-12 和 IFN-γ 处理加重了感染小鼠巨噬细胞中 CXCL8 和 CXCR1 的表达。TNF-α+IFN-γ 治疗是一氧化氮释放的主要诱导剂，并介导最大的细菌杀伤。IL-12+TNF-α 治疗通过增加 TNFR1、IL-1R 和 NF-κB 激活，最有效地增加 ROS，上调 CXCL8/CXCR1 的表达。IL-10 逆转了外源性细胞因子的作用，但也损害了腹腔灌洗中的细菌清除现象。IL-12+TNF-α+IL-10 治疗最有效地改善氧化应激，降低 CXCL8 的释放和 TNFR1、IL-1R 和 NF-κB 的表达水平。总之，IL-12+TNF-α+IL-10 治疗通过下调 TNFR1-IL-1R-NF-κB 通路，减轻了腹腔巨噬细胞中 CXCL8/CXCR1 的表达和炎症信号，减轻了金黄色葡萄球菌感染后的炎症后遗症。
