Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia.
Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia.
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金黄色葡萄球菌是严重肺炎的主要原因。多种促炎信号机制被激活，以招募免疫细胞进入呼吸道，以响应金黄色葡萄球菌。我们发现，IL-16，一种与CD4结合的T细胞细胞因子，可以被金黄色葡萄球菌激活，特别是被蛋白A(SpA)激活，而且比革兰氏阴性病原体或内毒素激活的程度要大得多。IL-16的产生涉及多种信号，包括连接TNFR家族成员或EGFR，这两个受体都是SPA的受体，并产生钙离子通量来激活钙蛋白酶和caspase-3。虽然人的呼吸道上皮细胞、血管内皮细胞、THP-1和Jurkat T细胞在体外对金黄色葡萄球菌有反应而释放IL-16，但在肺炎的小鼠模型中，CD4+细胞是IL-16的主要来源，提示参与了自分泌信号通路。IL-16的产生有助于肺损伤，因为IL-16的中和增强了金黄色葡萄球菌的清除，并导致金黄色葡萄球菌肺炎的肺病理减轻。我们的结果表明，金黄色葡萄球菌激活TNFR1和钙/钙蛋白酶信号通路的能力有助于T细胞的激活和急性肺炎的过度炎症。
Staphylococcus aureus is a major cause of severe pneumonia. Multiple mechanisms of proinflammatory signaling are activated to recruit immune cells into the airway in response to S. aureus. We found that IL-16, a T cell cytokine that binds CD4, is potently activated by S. aureus, specifically by protein A (SpA), and to a much greater extent than by Gram negative pathogens or LPS. IL-16 production involved multiple signals including ligation of TNFR family members or EGFR, both receptors for SpA and generation of Ca2+ fluxes to activate calpains and caspase-3. Although human airway epithelial cells, vascular endothelial cells, THP-1 and Jurkat T cells released IL-16 in response to S. aureus in vitro, in a murine model of pneumonia, CD4+ cells were the major source of IL-16 suggesting the involvement of an autocrine signaling pathway. The production of IL-16 contributed to lung damage as neutralization of IL-16 enhanced S. aureus clearance and resulted in diminished lung pathology in S. aureus pneumonia. Our results suggest that the ability of S.aureus to activate TNFR1 and Ca2+/calpain signaling contribute to T cell activation and excessive inflammation in the setting of acute pneumonia.
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