Transforming growth factor-β-activated kinase 1 (TAK1) is required for human FcγRIIIb-induced neutrophil extracellular trap (NET) formation

• Main Authors: Omar Rafael Alemán, Nancy Mora, Ricarda Cortes-Vieyra, Eileen Uribe-Querol, CARLOS ROSALES
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2016-07-01
• Series: Frontiers in Immunology
• Subjects: DNA; Inflammation; ERK; Neutrophil; immunoglobulin; Immunoreceptor
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00277/full

Neutrophils (PMN) are the most abundant leukocytes in the blood. PMN migrate from the circulation to sites of infection, where they are responsible for antimicrobial functions. PMN use phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. Several stimuli, including bacteria, fungi, and parasites, and some pharmacological compounds such as PMA are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. Recently, it was reported that FcγRIIIb crosslinking induced NET formation similarly to PMA stimulation. Direct crosslinking of FcγRIIA or integrins did not promote NET formation. FcγRIIIb-induced NET formation presented different kinetics from PMA-induced NET formation, suggesting differences in signaling. Because FcγRIIIb also induces a strong activation of ERK and nuclear factor Elk-1, and the transforming growth factor-β-activated kinase 1 (TAK1) has recently been implicated in ERK signaling, in the present report, we explored the role of TAK1 in the signaling pathway activated by FcγRIIIb leading to NET formation. FcγRIIIb was stimulated by specific monoclonal antibodies and NET formation was evaluated in the presence or absence of pharmacological inhibitors. The antibiotic LL Z1640-2, a selective inhibitor of TAK1 prevented FcγRIIIb-induced, but not PMA-induced NET formation. Both PMA and FcγRIIIb crosslinkng induced phosphorylation of ERK. But, LL Z1640-2 only inhibited the FcγRIIIb-mediated activation of ERK. Also, only FcγRIIIb, similarly to transforming growth factor-β, induced TAK1 phosphorylation. A MEK (ERK kinase) specific inhibitor was able to prevent ERK phosphorylation induced by both PMA and FcγRIIIb. These data show for the first time that FcγRIIIb crosslinking activates TAK1 and that this kinase is required for triggering the MEK/ERK signaling pathway to NETosis.