Mycobacterial cord factor enhances migration of neutrophil ‐like HL‐60 cells by prolonging AKT phosphorylation

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 this activity remain unknown. We hypothesized that TDM stimulates transendothelial migration of neutrophils, which are the first immune cells to infiltrate the tissue upon infection. Here, we show that TDM enhances N‐formylmethionyl‐leucyl‐phenylalanine (fMLP)‐induced chemotaxis and transendothelial movement by prolonging AKT phosphorylation in human neutrophils. TDM induced the expression of Mincle, a receptor for TDM, and induced the secretion of pro‐inflammatory cytokines and chemokines in differentiated HL‐60 (dHL‐60) cells. Using two‐ and three‐dimensional neutrophil migration assays, TDM‐stimulated neutrophils showed increased fMLP‐induced chemotaxis and transendothelial migration. Interestingly, AKT, a crucial kinase for neutrophil polarization and chemotaxis, showed prolonged phosphorylation at serine 473 following fMLP stimulation of TDM‐activated neutrophils. Taken together, these data suggest that TDM modulates the transendothelial migration of neutrophils upon mycobacterial infection through prolonged AKT phosphorylation. AKT might therefore be a promising therapeutic target for enhancing immune responses to mycobacterial infection.
Source: Microbiology and Immunology - Category: Microbiology Authors: Tags: Original Article Source Type: research