NDLI: A novel mechanism underlying the basic defensive response of macrophages against Mycobacterium infection.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Shimada, Tomokazu Makino, Kimiko Kumokoshi, Shunsuke Doi, Norio Shimokawa, Noriko Fujisawa, Tatsuya Terada, Hiroshi Iyoda, Takuya Fukatsu, Yoshinobu Matsunaga, Takuya Takada, Muneaki Fukai, Fumio
Description	Author Affiliation: Iyoda T ( Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan)
Abstract	Following inhalation of Mycobacterium tuberculosis, including bacillus Calmette-Guérin (BCG), pathogens enter and grow inside macrophages by taking advantage of their phagocytic mechanisms. Macrophages often fail to eliminate intracellular M. tuberculosis, leading to the induction of host macrophage death. Despite accumulating evidence, the molecular mechanisms underlying M. tuberculosis infection-induced cell death remain controversial. In this study, we show the involvement of two distinct pathways triggered by TLR2 and ß2 integrin in BCG infection-induced macrophage apoptosis. First, BCG infection induced activation of ERK1/2, which in turn caused phosphorylation/activation of the proapoptotic protein Bim in mouse macrophage-like Raw 264.7 cells. BCG-infected Raw cells treated with U0126, an MEK/ERK inhibitor, led to the suppression of Bim phosphorylation alongside a remarkable increase in the number of viable macrophages. Small interfering RNA-mediated knockdown of Bim rescued the macrophages from the apoptotic cell death induced by BCG infection. Stimulation with Pam3CSK, a TLR2 agonist, induced macrophage apoptosis with a concomitant increase in the phosphorylation/activation of MEK/ERK and Bim. These observations indicate the important role of the TLR2/MEK/ERK/Bim pathway in BCG infection-induced macrophage apoptosis. Second, we used the ß2 integrin agonists C3bi and fibronectin to show that the ß2 integrin-derived signal was involved in BCG infection-induced apoptosis, independent of MEK/ERK activation. Interestingly, latex beads coated with Pam3CSK and C3bi were able to induce apoptosis in macrophages to the same extent and specificity as that induced by BCG. Taken together, two distinct pattern-recognition membrane receptors, TLR2 and ß2 integrin, acted as triggers in BCG infection-induced macrophage apoptosis, in which MEK/ERK activation played a crucial role following the engagement of TLR2.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	9
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Apoptosis Immunology Macrophages Mycobacterium Infections Signal Transduction Animals Antigens, Cd18 Metabolism Flow Cytometry Immunoprecipitation In Situ Nick-end Labeling Microbiology Mice Microscopy, Confocal Mycobacterium Tuberculosis Rna, Small Interfering Toll-like Receptor 2 Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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