TNF induces neutrophil adhesion via formin-dependent cytoskeletal reorganization and activation of beta-integrin function

Autor(es)

Antoniellis Silveira, Angelica Aparecida ^[1] ; Dominical, Venina Marcela ^[1] ; Almeida, Camila Bononi ^[1] ; Chweih, Hanan ^[1] ; Ferreira, Jr., Wilson Alves ^[1] ; Vicente, Cristina Pontes ^[2] ; Maranhao Costa, Fabio Trindade ^[3] ; Werneck, Claudio C. ^[4] ; Costa, Fernando Ferreira ^[1] ; Conran, Nicola ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Sch Med, Hematol & Hemotherapy Ctr, Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Biol Inst, Dept Struct & Funct Biol, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Inst Biol, Genet Evolut & Bioagents, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Leukocyte Biology; v. 103, n. 1, p. 87-98, JAN 2018.
• Citações Web of Science: 3

Resumo

Although essential for inflammatory responses, leukocyte recruitment to blood vessel walls in response to inflammatory stimuli, such as TNF-alpha, can contribute to vascular occlusion in inflammatorydiseases, including atherosclerosis. We aimed to further characterize the mechanisms by which TNF stimulates adhesive and morphologic alterations in neutrophils. Microfluidic and intravital assays confirmed the potent effect that TNF has on human and murine neutrophil adhesion and recruitment in vitro and in vivo, respectively. Inhibition of actin polymerization by cytochalasin D significantly diminished TNF-induced human neutrophil adhesion in vitro and abolished TNF-induced membrane alterations and cell spreading. In contrast, TNF-induced increases in.. beta 2-integrin (Mac-1 and LFA-1) expression was not significantly altered by actin polymerization inhibition. Consistent with a role for cytoskeletal rearrangements in TNF-induced adhesion, TNF augmented the activity of the Rho GTPase, RhoA, in human neutrophils. However, inhibition of the major RhoA effector protein, Rho kinase (ROCK), by Y-27632 failed to inhibit TNF-induced neutrophil adhesion. In contrast, the formin FH2 domain inhibitor, SMIFH2, abolished TNF-induced human neutrophil adhesion and diminished leukocyte recruitment in vivo. SMIFH2 also inhibited TNF-induced cytoskeletal reorganization in human neutrophils and abolished the alterations in.. beta 2-integrin expression elicited by TNF stimulation. As such, Rho GTPase/mDia formin-mediated cytoskeletal reorganization appears to participate in the orchestration of TNF-induced neutrophil-adhesive interactions, possiblymediated by formin-mediated actin nucleation and subsequent modulation of.. beta 2-integrin activity on the neutrophil surface. This pathway may represent a pharmacologic target for reducing leukocyte recruitment in inflammatory diseases. (AU)

• Processo FAPESP: 12/22048-2 - Investigação das propriedades pro-inflamatórias do TNF-alfa e do heme em leucócitos in vitro e in vivo.
• Beneficiário: Angélica Aparecida Antoniellis Silveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/19916-7 - Avaliação da síntese de fibras elásticas em cultura de células obtidas de camundongos deficientes em fibrilina-1: estudo do efeito do Losartan
• Beneficiário: Claudio Chrysostomo Werneck
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/19173-5 - Inflamação vascular: mecanismos fisiopatológicos de indução e vias de ativação celular
• Beneficiário: Nicola Amanda Conran Zorzetto
• Modalidade de apoio: Auxílio à Pesquisa - Regular