title: Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway.
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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Wook-Bin
authors.initials: WB
authors.lastname: Lee
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Kang
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Yan
authors.forename: Myeong Sup
authors.initials: MS
authors.lastname: Lee
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Jeon
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003311:Cord Factors / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015769:Granuloma, Respiratory Tract / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D039481:CD11b Antigen; D018821:CD18 Antigens; C113583:Clecsf8 protein, mouse; D003311:Cord Factors; D037181:Lectins, C-Type; D008565:Membrane Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D011494:Protein Kinases