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NF-κB Activation Controls Phagolysosome Fusion-Mediated Killing of Mycobacteria by Macrophages

2008; American Association of Immunologists; Volume: 181; Issue: 4 Linguagem: Inglês

10.4049/jimmunol.181.4.2651

1550-6606

Maximiliano G. Gutiérrez, Bibhuti B. Mishra, Luísa Jordão, Edith Elliott, Elsa Anes, Gareth Griffiths,

Ginseng Biological Effects and Applications

Abstract Macrophages can potentially kill all mycobacteria by poorly understood mechanisms. In this study, we explore the role of NF-κB in the innate immune response of macrophages against Mycobacterium smegmatis, a nonpathogenic mycobacterium efficiently killed by macrophages, and Mycobacterium avium which survives within macrophages. We show that infection of macrophages with M. smegmatis induces an activation of NF-κB that is essential for maturation of mycobacterial phagosomes and bacterial killing. In contrast, the pathogenic M. avium partially represses NF-κB activation. Using microarray analysis, we identified many lysosomal enzymes and membrane-trafficking regulators, including cathepsins, LAMP-2 and Rab34, were regulated by NF-κB during infection. Our results argue that NF-κB activation increases the synthesis of membrane trafficking molecules, which may be rate limiting for regulating phagolysosome fusion during infection. The direct consequence of NF-κB inhibition is the impaired delivery of lysosomal enzymes to M. smegmatis phagosomes and reduced killing. Thus, the established role of NF-κB in the innate immune response can now be expanded to include regulation of membrane trafficking during infection.