Centro de Estudios Biomédicos, Aplicados y Desarrollo (CEBBAD), Departamento de Ciencias Biológicas y Biomédicas, Universidad Maimonides, Buenos Aires, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Front Immunol. 2021 Feb 22;11:524180. doi: 10.3389/fimmu.2020.524180. eCollection 2020.
The type 1 TNF-α receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils. Considering that TNFR1 signals protein A (SpA), the aim of this study was to explore the interaction of this bacterial surface protein with neutrophils and keratinocytes to underscore the signaling pathways that may determine the fate of these innate immune cells in the infected tissue during staphylococcal skin infections. Using human neutrophils cultured and isogenic staphylococcal strains expressing or not protein A, we demonstrated that SpA is a potent inducer of IL-8 in neutrophils and that the induction of this chemokine is dependent on the SpA-TNFR1 interaction and p38 activation. In addition to IL-8, protein A induced the expression of TNF-α and MIP-1α highlighting the importance of SpA in the amplification of the inflammatory response. Protein A contributed to reduce neutrophil mortality prolonging their lifespan upon the encounter with . Signaling initiated by SpA modulated the type of neutrophil cell death and during skin and soft tissue infections (SSTI) triggering the apoptotic pathway instead of necrosis. Moreover, SpA induced pro-inflammatory cytokines in keratinocytes, modulating their survival and preventing the exacerbated necrosis and ulceration of the epithelium during SSTI . Taken together, these results highlight the importance of the inflammatory signaling induced by protein A in neutrophils and skin epithelial cells. The ability of protein A to modulate the neutrophil/epithelial cell death program in the skin is of clinical relevance considering that lysis of neutrophils and epithelial cells will promote an intense inflammatory response and contribute to tissue damage, a non-desirable feature of complicated SSTI.
1 型肿瘤坏死因子-α 受体 (TNFR1) 在启动中性粒细胞中促炎和促凋亡信号级联反应中具有核心作用。鉴于 TNFR1 信号蛋白 A (SpA)，本研究旨在探索这种细菌表面蛋白与中性粒细胞和角质形成细胞的相互作用，以强调可能决定金黄色葡萄球菌皮肤感染组织中这些固有免疫细胞命运的信号通路。使用培养的人中性粒细胞和表达或不表达蛋白 A 的同源性葡萄球菌株，我们证明 SpA 是中性粒细胞中 IL-8 的有效诱导剂，并且这种趋化因子的诱导依赖于 SpA-TNFR1 相互作用和 p38 激活。除了 IL-8，蛋白 A 还诱导 TNF-α 和 MIP-1α 的表达，突出了 SpA 在炎症反应放大中的重要性。蛋白 A 通过延长与 接触时中性粒细胞的寿命，有助于减少中性粒细胞的死亡率。SpA 启动的信号转导调节中性粒细胞细胞死亡的类型，在皮肤和软组织感染 (SSTI) 中触发凋亡途径而不是坏死。此外，SpA 在角质形成细胞中诱导促炎细胞因子，调节其存活，并防止 SSTI 期间上皮细胞的过度坏死和溃疡。总之，这些结果强调了蛋白 A 在中性粒细胞和皮肤上皮细胞中诱导炎症信号的重要性。考虑到中性粒细胞和上皮细胞的裂解将促进强烈的炎症反应并导致组织损伤，蛋白 A 调节中性粒细胞/上皮细胞死亡程序在临床上具有相关性，这是复杂 SSTI 的一个非理想特征。
