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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-\u03baB pathway in BLP-tolerised macrophages. Importantly, activation of NF-\u03baB pathway is critical for BLP tolerance-enhanced antimicrobial activity, as deactivation of NF-\u03baB in BLP-tolerised macrophages impaired phagosome maturation and intracellular killing of the ingested bacteria. Finally, activation of NF-\u03baB 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-\u03baB 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-\u03baB pathway is essential for BLP tolerance-augmented antimicrobial activity in innate phagocytes and depends primarily on both NOD1 and NOD2.<\/jats:p>","DOI":"10.1038\/srep40418","type":"journal-article","created":{"date-parts":[[2017,1,12]],"date-time":"2017-01-12T10:18:14Z","timestamp":1484216294000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["NF-\u03baB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection"],"prefix":"10.1038","volume":"7","author":[{"given":"Jinghua","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan","family":"Blankson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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