Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
Sci Rep. 2017 Jan 12;7:40418. doi: 10.1038/srep40418.
Tolerance to bacterial components represents an essential regulatory mechanism during bacterial infection. Bacterial lipoprotein (BLP)-induced tolerance confers protection against microbial sepsis by attenuating inflammatory responses and augmenting antimicrobial activity in innate phagocytes. It has been well-documented that BLP tolerance-attenuated proinflammatory cytokine production is associated with suppressed TLR2 signalling pathway; however, the underlying mechanism(s) involved in BLP tolerance-enhanced antimicrobial activity is unclear. Here we report that BLP-tolerised macrophages exhibited accelerated phagosome maturation and enhanced bactericidal activity upon bacterial infection, with upregulated expression of membrane-trafficking regulators and lysosomal enzymes. Notably, bacterial challenge resulted in a strong activation of NF-κB pathway in BLP-tolerised macrophages. Importantly, activation of NF-κB pathway is critical for BLP tolerance-enhanced antimicrobial activity, as deactivation of NF-κB in BLP-tolerised macrophages impaired phagosome maturation and intracellular killing of the ingested bacteria. Finally, activation of NF-κB pathway in BLP-tolerised macrophages was dependent on NOD1 and NOD2 signalling, as knocking-down NOD1 and NOD2 substantially inhibited bacteria-induced activation of NF-κB and overexpression of Rab10 and Acp5, two membrane-trafficking regulators and lysosomal enzymes contributed to BLP tolerance-enhanced bactericidal activity. These results indicate that activation of NF-κB pathway is essential for BLP tolerance-augmented antimicrobial activity in innate phagocytes and depends primarily on both NOD1 and NOD2.
耐受细菌成分是细菌感染过程中一种重要的调节机制。细菌脂蛋白 (BLP) 诱导的耐受通过减轻炎症反应和增强先天吞噬细胞的抗菌活性来保护免受微生物败血症的侵害。有充分的证据表明，BLP 耐受减弱促炎细胞因子的产生与 TLR2 信号通路的抑制有关；然而，BLP 耐受增强抗菌活性的潜在机制尚不清楚。在这里，我们报告说，BLP 耐受的巨噬细胞在细菌感染后表现出更快的吞噬体成熟和增强的杀菌活性，同时上调了膜运输调节剂和溶酶体酶的表达。值得注意的是，细菌挑战导致 BLP 耐受的巨噬细胞中 NF-κB 途径强烈激活。重要的是，NF-κB 途径的激活对于 BLP 耐受增强的抗菌活性至关重要，因为 BLP 耐受的巨噬细胞中 NF-κB 的失活会损害吞噬体成熟和吞噬的细菌的细胞内杀伤。最后，BLP 耐受的巨噬细胞中 NF-κB 途径的激活依赖于 NOD1 和 NOD2 信号，因为敲低 NOD1 和 NOD2 会大大抑制细菌诱导的 NF-κB 激活和上调 Rab10 和 Acp5 的表达，这两种膜运输调节剂和溶酶体酶有助于 BLP 耐受增强的杀菌活性。这些结果表明，NF-κB 途径的激活对于先天吞噬细胞中 BLP 耐受增强的抗菌活性是必不可少的，主要依赖于 NOD1 和 NOD2。
