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

PLoS Pathog. 2012;8(4):e1002614. doi: 10.1371/journal.ppat.1002614. Epub 2012 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Adjuvants, Immunologic
  • CD11b Antigen
  • CD18 Antigens
  • Clecsf8 protein, mouse
  • Cord Factors
  • Lectins, C-Type
  • Membrane Proteins
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Protein Kinases