title: Transforming Growth Factor-β-Activated Kinase 1 Is Required for Human FcγRIIIb-Induced Neutrophil Extracellular Trap Formation.
abstract: Neutrophils (PMNs) are the most abundant leukocytes in the blood. PMN migrates from the circulation to sites of infection where they are responsible for antimicrobial functions. PMN uses 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 Phorbol 12-myristate 13-acetate (PMA), are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. Recently, it was reported that FcγRIIIb cross-linking induced NET formation similarly to PMA stimulation. Direct cross-linking 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 extracellular signal-regulated kinase (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 cross-linking 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 cross-linking activates TAK1, and that this kinase is required for triggering the MEK/ERK signaling pathway to NETosis.
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
authors.forename: Omar Rafael
authors.initials: OR
authors.lastname: Alemán
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mora
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Cortes-Vieyra
authors.affiliation: División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
authors.forename: Eileen
authors.initials: E
authors.lastname: Uribe-Querol
authors.affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rosales
keywords: DNA; ERK; TAK1; immunoglobulin; immunoreceptor; inflammation; neutrophil