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Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway

Authors
 Wook-Bin Lee  ;  Ji-Seon Kang  ;  Ji-Jing Yan  ;  Myeong Sup Lee  ;  Bo-Young Jeon  ;  Sang-Nae Cho  ;  Young-Joon Kim 
Citation
 PLOS PATHOGENS, Vol.8(4) : e1002614, 2012 
Journal Title
 PLOS PATHOGENS 
ISSN
 1553-7366 
Issue Date
2012
MeSH
Adjuvants, Immunologic/adverse effects* ; Adjuvants, Immunologic/chemistry ; Adjuvants, Immunologic/pharmacology ; Animals ; CD11b Antigen/genetics ; CD11b Antigen/immunology ; CD11b Antigen/metabolism ; CD18 Antigens/genetics ; CD18 Antigens/immunology ; CD18 Antigens/metabolism ; Cord Factors/adverse effects* ; Cord Factors/chemistry ; Cord Factors/pharmacology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Gene Expression Regulation/immunology ; Granuloma, Respiratory Tract/chemically induced ; Granuloma, Respiratory Tract/genetics ; Granuloma, Respiratory Tract/immunology ; Granuloma, Respiratory Tract/metabolism ; Granuloma, Respiratory Tract/pathology ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Lectins, C-Type/metabolism* ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Membrane Proteins/metabolism* ; Mice ; Mice, Knockout ; Mycobacterium tuberculosis/chemistry ; Mycobacterium tuberculosis/metabolism ; Neutrophil Infiltration/drug effects* ; Neutrophil Infiltration/genetics ; Neutrophil Infiltration/immunology ; Neutrophils/immunology ; Neutrophils/metabolism* ; Neutrophils/pathology ; Pneumonia/chemically induced* ; Pneumonia/genetics ; Pneumonia/immunology ; Pneumonia/metabolism* ; Pneumonia/pathology ; Protein Kinases/genetics ; Protein Kinases/immunology ; Protein Kinases/metabolism ; Signal Transduction/drug effects* ; Signal Transduction/genetics ; Signal Transduction/immunology ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 2/immunology ; Toll-Like Receptor 2/metabolism ; Tuberculosis, Pulmonary/genetics ; Tuberculosis, Pulmonary/immunology ; Tuberculosis, Pulmonary/metabolism ; Tuberculosis, Pulmonary/pathology
Keywords
Adjuvants, Immunologic/adverse effects* ; Adjuvants, Immunologic/chemistry ; Adjuvants, Immunologic/pharmacology ; Animals ; CD11b Antigen/genetics ; CD11b Antigen/immunology ; CD11b Antigen/metabolism ; CD18 Antigens/genetics ; CD18 Antigens/immunology ; CD18 Antigens/metabolism ; Cord Factors/adverse effects* ; Cord Factors/chemistry ; Cord Factors/pharmacology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Gene Expression Regulation/immunology ; Granuloma, Respiratory Tract/chemically induced ; Granuloma, Respiratory Tract/genetics ; Granuloma, Respiratory Tract/immunology ; Granuloma, Respiratory Tract/metabolism ; Granuloma, Respiratory Tract/pathology ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Lectins, C-Type/metabolism* ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Membrane Proteins/metabolism* ; Mice ; Mice, Knockout ; Mycobacterium tuberculosis/chemistry ; Mycobacterium tuberculosis/metabolism ; Neutrophil Infiltration/drug effects* ; Neutrophil Infiltration/genetics ; Neutrophil Infiltration/immunology ; Neutrophils/immunology ; Neutrophils/metabolism* ; Neutrophils/pathology ; Pneumonia/chemically induced* ; Pneumonia/genetics ; Pneumonia/immunology ; Pneumonia/metabolism* ; Pneumonia/pathology ; Protein Kinases/genetics ; Protein Kinases/immunology ; Protein Kinases/metabolism ; Signal Transduction/drug effects* ; Signal Transduction/genetics ; Signal Transduction/immunology ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 2/immunology ; Toll-Like Receptor 2/metabolism ; Tuberculosis, Pulmonary/genetics ; Tuberculosis, Pulmonary/immunology ; Tuberculosis, Pulmonary/metabolism ; Tuberculosis, Pulmonary/pathology
Abstract
Trehalose 6,6'-dimycolate (TDM), a cord factor of Mycobacterium tuberculosis (Mtb), is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK). Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle⁻/⁻ mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils during anti-mycobacterial responses.
Files in This Item:
T201201068.pdf Download
DOI
22496642
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Cho, Sang Nae(조상래)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/91747
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