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

PLoS Pathogens

Ji-Jing Yan¹  Ji-Seon Kang¹  Young-Joon Kim¹  Wook-Bin Lee¹  Myeong Sup Lee¹  Sang-Nae Cho²  Bo-Young Jeon² 

[1] Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea;Department of Microbiology and Institute of Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, Republic of Korea

关键词: Neutrophils;    Mycobacterium tuberculosis;    Inflammation;    Granulomas;    Macrophages;    Immune response;    Immune receptor signaling;    Flow cytometry;   

DOI  :  10.1371/journal.ppat.1002614

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY