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* Department of Microbiology and
Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea;
Glycomics Team, Korea Basic Science Institute, Daejeon, South Korea;
Disease Model Research Center and
¶ Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea; and
|| Division of Molecular Life Sciences, Center for Cell Signaling Research, Ewha Womans University, Seoul, South Korea
Gp91phox/NADPH oxidase (NOX) 2 is the main catalytic component of NOX, which mediates the phagocytic killing of ingested pathogens via the production of reactive oxygen species (ROS). However, Mycobacterium tuberculosis (Mtb) is relatively resistant to the microbicidal effects of ROS. Thus, the exact roles of NOX2 in the innate immune control against Mtb infection are not fully resolved. In this study, we show that NOX2 is essential for TLR2-dependent inflammatory responses and 1,25-dihydroxyvitamin D3 (1,25D3)-mediated antimicrobial activity against Mtb via cathelicidin expression. NOX2-null macrophages prominently abrogated Mtb-induced ROS production and inflammatory signaling activation in a TLR2-dependent manner. Mtb triggered a physical association between NOX2 and TLR2. In addition, the knockdown of NOX2 inhibited 1,25D3-triggered antimicrobial activity against viable Mtb through the modulation of cathelicidin expression in human macrophages. Treatment of NOX2 knocked down cells with cathelicidin restored the 1,25D3-induced antimicrobial effect, suggesting that the NOX2-dependent induction of cathelicidin in macrophages is part of a defensive strategy against Mtb. Furthermore, cathelicidin expression was required for the Mtb-induced release of ROS and the production of proinflammatory cytokines/chemokines, indicating a positive circuit of inflammation in response to Mtb. Our data collectively demonstrate a novel regulatory mechanism for TLR2-dependent innate responses to Mtb involving crosstalk between NOX2 and TLR2 and the expression of cathelicidin.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Korea Science and Engineering Foundation through the Infection Signaling Network Research Center (Grant R13-2007-020-01000-0) at Chungnam National University.
2 Address correspondence and reprint requests to Dr. Eun-Kyeong Jo, Department of Microbiology, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jungku, Daejeon 301-747, South Korea. E-mail address: hayoungj{at}cnu.ac.kr
3 Abbreviations used in this paper: ROS, reactive oxygen species; BLP, bacterial lipoprotein; BMDM, bone marrow-derived macrophage; CGD, chronic granulomatous disease; 1,25D3, 1,25-dihydroxyvitamin D3; DHE, dihydroethidium; DPI, diphenyleneiodonium; h, human (prefix); HA, hemagglutinin; HK-Mtb, heat-killed Mtb; IKK, I
B kinase; KO, knockout; LL-37, 37-aa cathelicidin peptide; MDM, monocyte-derived macrophage; MOI, multiplicity of infection; Mtb, Mycobacterium tuberculosis; NAC, N-acetylcysteine; NOX, NADPH oxidase; PPD, purified protein derivative; SAPK, stress-activated protein kinase; siCat, cathelicidin siRNA; siNS, nonspecific control siRNA; siNOX2, NOX2-specific siRNA; siRNA, small interfering RNA; TB, tuberculosis; TIR, Toll/IL-1R; WT, wild type.
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