title: NF-κB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection.
abstract: 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.
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Blankson
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shuqi
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Cai
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
authors.forename: H Paul
authors.initials: HP
authors.lastname: Redmond
authors.affiliation: Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
authors.forename: Jiang Huai
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D020868:Gene Silencing; D007108:Immune Tolerance; D008074:Lipoproteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D015854:Up-Regulation; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D008074:Lipoproteins; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C520736:Rab10 protein, mouse; D020691:rab GTP-Binding Proteins