Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle

By E. Ishikawa, Tetsuaki Ishikawa, Y. Morita, K. Toyonaga, H. Yamada, O. Takeuchi, T. Kinoshita, Shizuo Akira, Y. Yoshikai, S. Yamasaki. Journal of Experimental Medicine, 2009

738 citations recorded by the source corpus.

Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, which contains various unique components that affect the host immune system. Trehalose-6,6′-dimycolate (TDM; also called cord factor) is a mycobacterial cell wall glycolipid that is the most studied immunostimulatory component of M. tuberculosis. Despite five decades of research on TDM, its host receptor has not been clearly identified. Here, we demonstrate that macrophage inducible C-type lectin (Mincle) is an essential receptor for TDM. Heat-killed mycobacteria activated Mincle-expressing cells, but the activity was lost upon delipidation of the bacteria; analysis of the lipid extracts identified TDM as a Mincle ligand. TDM activated macrophages to produce inflammatory cytokines and nitric oxide, which are completely suppressed in Mincle-deficient macrophages. In vivo TDM administration induced a robust elevation of inflammatory cytokines in sera and characteristic lung inflammation, such as granuloma formation. However, no TDM-induced lung granuloma was formed in Mincle-deficient mice. Whole mycobacteria were able to activate macrophages even in MyD88-deficient background, but the activation was significantly diminished in Mincle/MyD88 double-deficient macrophages. These results demonstrate that Mincle is an essential receptor for the mycobacterial glycolipid, TDM.

Subfields: Epidemiology, Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/f6842a5663338ac7b2b76bffb971b87ce897cfbb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. Taro Kawai
2. A. Mócsai
3. Shizuo Akira
4. R. Medzhitov

In Immunology

1. Shizuo Akira
2. Taro Kawai
3. R. Coffman
4. A. Sher
5. R. Seder
6. K. Futosi
7. Szabina Fodor
8. A. Mócsai

In Infectious Diseases

1. Michael A. Fischbach
2. Taro Kawai
3. Mohamed S. Donia
4. Shizuo Akira

Citations in the corpus

• Vaccine Adjuvants: Putting Innate Immunity to Work (2010, background): “macrophages andCD8 , but not CD8, DC subsets (Iwasaki and Medzhitov, 2004).”
• Small Molecules from the Human Microbiota (2015, positive): “Another glycolipid derivative of mycolic acid, trehalose-6,6-dimycolate, is a potent immune elicitor that binds to the C-type lectin Mincle to induce macrophage activation and a T cell response characteristic of vaccination (84).”
• Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. (2011, background): “deficient mice (Ishikawa et al., 2009; Schoenen et al., 2010).”
• Standard methods for physiology and biochemistry research in Apis mellifera (2013, methodology): “After taking the glucose readings, pipette 0.5 µl of the trehalase enzyme into each cuvette or well of the microplate including the wells containing the glucose standards (Flatt et al., 2008; Ishikawa et al., 2009).”
• Neutrophil cell surface receptors and their intracellular signal transduction pathways (2013, background): “Mincle is a multifunctional receptor recognizing Malassezia fungi [208], mycobacterial structures [203,209] and cytoplasmic danger signals (such as SAP130) [210].”
• The SYK tyrosine kinase: a crucial player in diverse biological functions (2010, background): “Both CLEC6A–SYK and CLEC4E–SYK signalling induce CARD9- and NF-κB-mediated pro-inflammatory responses, which promote adaptive immunity and robust T H 17 cell response”