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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: Journal of Leukocyte Biology; v. 103, n. 1, p. 87-98, JAN 2018.
• Web of Science Citations: 3

Abstract

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)

• FAPESP's process: 12/22048-2 - Investigation into the pro-inflammatory properties of TNF-alpha and heme in leukocytes in vitro and in vivo.
• Grantee: Angélica Aparecida Antoniellis Silveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/19916-7 - Evaluation on elastic fiber synthesis in cell culture obtained from fibrillin-1 defficient mice: Losartan's effect studies
• Grantee: Claudio Chrysostomo Werneck
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/19173-5 - Vascular inflammation: pathophysiological mechanisms of induction and pathways of cellular activation
• Grantee: Nicola Amanda Conran Zorzetto
• Support Opportunities: Regular Research Grants