CLEC9A modulates macrophage-mediated neutrophil recruitment in response to heat-killed Mycobacterium tuberculosis H37Ra

• Published in: PloS one Vol. 12; no. 10; p. e0186780
• Main Authors: Cheng, An-Chieh, Yang, Kuang-Yao, Chen, Nien-Jung, Hsu, Tsui-Ling, Jou, Ruwen, Hsieh, Shie-Liang, Tseng, Ping-Hui
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.10.2017; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Animals; Antigens; Bacteria; Biochemistry; Biology and Life Sciences; Cell activation; Cell Line; Cell walls; Chemokines; Cytokines; Development and progression; Fc receptors; Fusion protein; Gene Knockdown Techniques; Genetic aspects; Genomics; Granulocytes; Hot Temperature; Humans; IL-1β; Immune response; Immune system; Immunity; Immunology; Infections; Infectious diseases; Infiltration; Innate immunity; Kinases; Lectins; Lectins, C-Type - genetics; Lectins, C-Type - physiology; Leukemia; Life sciences; Lungs; Macrophages; Macrophages - enzymology; Macrophages - physiology; Male; MAP kinase; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Molecular biology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - physiology; Neutrophils; Neutrophils - cytology; Pathogenesis; Pathogenicity; Pathogens; Pattern recognition; Pattern recognition receptors; Physiological aspects; Polysaccharides; Protein Kinases - metabolism; Proteins; Receptors; Receptors, Mitogen - genetics; Receptors, Mitogen - physiology; Research and Analysis Methods; Signal Transduction; Signaling; Syk protein; Tuberculosis; Taiwan
• DOI: 10.1371/journal.pone.0186780
• ISSN: 1932-6203

Tuberculosis is a fatal human infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis) that is prevalent worldwide. Mycobacteria differ from other bacteria in that they have a cell wall composed of specific surface glycans that are the major determinant of these organisms' pathogenicity. The interaction of M. tuberculosis with pattern recognition receptors (PRRs), in particular C-type lectin receptors (CLRs), on the surface of macrophages plays a central role in initiating innate and adaptive immunity, but the picture as a whole remains a puzzle. Defining novel mechanisms by which host receptors interact with pathogens in order to modulate a specific immune response is an area of intense research. In this study, based on an in vitro lectin binding assay, CLEC9A (DNGR-1) is identified as a novel CLR that binds with mycobacteria. Our results with CLEC9A-knocked down cells and a CLEC9A-Fc fusion protein as blocking agents show that CLEC9A is involved in the activation of SYK and MAPK signaling in response to heat-killed M. tuberculosis H37Ra treatment, and it then promotes the production of CXCL8 and IL-1β in macrophages. The CXCL8 and IL-1β secreted by the activated macrophages are critical to neutrophil recruitment and activation. In a in vivo mouse model, when the interaction between CLEC9A and H37Ra is interfered with by treatment with CLEC9A-Fc fusion protein, this reduces lung inflammation and cell infiltration. These findings demonstrate that CLEC9A is a specialized receptor that modulates the innate immune response when there is a mycobacterial infection.