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Mycobacterial cord factor enhances migration of neutrophil‐like HL‐60 cells by prolonging AKT phosphorylation
Authors:Wook‐Bin Lee  Ji‐Jing Yan  Ji‐Seon Kang  Seok Chung  Lark Kyun Kim
Institution:1. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea;2. Biomedical Research Institute, Seoul National University Hospital, Seoul 110‐744, Korea;3. Severance Biomedical Science Institute and BK21 PLUS Project to Medical Sciences, Severance Institute for Vascular and Metabolic Research, Gangnam Severance Hospital Yonsei University College of Medicine, Seoul 06230, Korea;4. School of Mechanical Engineering, Korea University, Seoul 02841, Korea
Abstract:
Trehalose 6,6′‐dimycolate (TDM), or cord factor, is a crucial stimulus of immune responses during Mycobacterium tuberculosis infection. Although TDM has immuno‐stimulatory properties, including adjuvant activity and the ability to induce granuloma formation, the mechanisms underlying these remain unknown. We hypothesized that TDM stimulates transendothelial migration of neutrophils, which are the first immune cells to infiltrate the tissue upon infection. In this study, it was shown that TDM enhances N‐formylmethionyl‐leucyl‐phenylalanine (fMLP)‐induced chemotaxis and transendothelial movement by prolonging AKT phosphorylation in human neutrophils. TDM induced expression of macrophage‐inducible C‐type lectin, a receptor for TDM, and induced secretion of pro‐inflammatory cytokines and chemokines in differentiated HL‐60 cells. In 2‐ and 3‐D neutrophil migration assays, TDM‐stimulated neutrophils showed increased fMLP‐induced chemotaxis and transendothelial migration. Interestingly, following fMLP stimulation of TDM‐activated neutrophils, AKT, a crucial kinase for neutrophil polarization and chemotaxis, showed prolonged phosphorylation at serine 473. Taken together, these data suggest that TDM modulates transendothelial migration of neutrophils upon mycobacterial infection through prolonged AKT phosphorylation. AKT may therefore be a promising therapeutic target for enhancing immune responses to mycobacterial infection.
Keywords:AKT  migration  neutrophil  trehalose dimycolate
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