Role for NOD2 in Mycobacterium tuberculosis‐induced iNOS expression and NO production in human macrophages

• Published in: Journal of leukocyte biology Vol. 97; no. 6; pp. 1111 - 1119
• Main Authors: Landes, Michelle B., Rajaram, Murugesan V. S., Nguyen, Huy, Schlesinger, Larry S.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01-06-2015
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - analogs & derivatives; Acetylmuramyl-Alanyl-Isoglutamine - pharmacology; Gene Expression Regulation; Host-Pathogen Interactions - immunology; Humans; Inflammation, Extracellular Mediators & Effector Molecules; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Mycobacterium bovis; Mycobacterium bovis - immunology; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - immunology; NF-kappa B - genetics; NF-kappa B - immunology; NF‐κB; nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - immunology; NLR; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - immunology; Primary Cell Culture; Signal Transduction; NF-κB; NLR; nitric oxide
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.3A1114-557R

Mycobacterium tuberculosis‐induced iNOS expression in human macrophages is NOD2‐dependent via the transcription factor NF‐κB.
M.tb, which causes TB, is a host‐adapted intracellular pathogen of macrophages. Macrophage intracellular PRRs, such as NOD proteins, regulate proinflammatory cytokine production in response to various pathogenic organisms. We demonstrated previously that NOD2 plays an important role in controlling the inflammatory response and viability of M.tb and Mycobacterium bovis BCG in human macrophages. Various inflammatory mediators, such as cytokines, ROS, and RNS, such as NO, can mediate this control. iNOS (or NOS2) is a key enzyme for NO production and M.tb control during infection of mouse macrophages; however, the role of NO during infection of human macrophages remains unclear, in part, as a result of the low amounts of NO produced in these cells. Here, we tested the hypothesis that activation of NOD2 by its ligands (MDP and GMDP, the latter from M.tb) plays an important role in the expression and activity of iNOS and NO production in human macrophages. We demonstrate that M.tb or M. bovis BCG infection enhances iNOS expression in human macrophages. The M.tb‐induced iNOS expression and NO production are dependent on NOD2 expression during M.tb infection. Finally, NF‐κB activation is required for NOD2‐dependent expression of iNOS in human macrophages. Our data provide evidence for a new molecular pathway that links activation of NOD2, an important intracellular PRR, and iNOS expression and activity during M.tb infection of human macrophages.