Interaction of kindlin-3 and β2-integrins differentially regulates neutrophil recruitment and NET release in mice

• Published in: Blood 2015-07, Vol.126 (3), p.373-377
• Main Authors: Xu, Zhen, Cai, Jiayi, Gao, Juan, White, Gilbert C., Chen, Fangyuan, Ma, Yan-Qing
• Format: Article
• Language: English
• Subjects: Animals; Blood Platelets - cytology; Blood Platelets - immunology; Blood Platelets - metabolism; Blotting, Western; CD18 Antigens - immunology; CD18 Antigens - metabolism; Cell Adhesion; Cells, Cultured; Cytoskeletal Proteins - immunology; Cytoskeletal Proteins - metabolism; Flow Cytometry; Mice; Neutrophil Infiltration - immunology; Neutrophils - cytology; Neutrophils - immunology; Neutrophils - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-03-636720

Kindlin-3 essentially supports integrin activation in blood cells. Absence of kindlin-3 in humans causes leukocyte adhesion deficiency-III characterized with severe bleeding disorder and recurrent infections. Previously, we generated kindlin-3 knock-in (K3KI) mice carrying an integrin-interaction disrupting mutation in kindlin-3 and verified the functional significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets. Here, using K3KI mice, we functionally evaluate the crosstalk between kindlin-3 and β2-integrins in neutrophils. Although the kindlin-3 mutant in K3KI neutrophils is normally expressed, its binding ability to β2-integrins in neutrophils is disabled. In vitro and in vivo analyses disclose that β2-integrin–mediated K3KI neutrophil adhesion and recruitment are significantly suppressed. Interestingly, the ability of releasing neutrophil extracellular traps (NETs) from K3KI neutrophils is also compromised. Substantially, a peptide derived from the integrin β2 cytoplasmic tail that can inhibit the interaction between kindlin-3 and β2-inegrins significantly jeopardizes NET release without affecting neutrophil adhesion and recruitment under the experimental conditions. These findings suggest that crosstalk between kindlin-3 and β2-integrins in neutrophils is required for supporting both neutrophil recruitment and NET release, but the involved regulatory mechanisms in these two cellular events might be differential, thus providing a novel therapeutic concept to treat innate immune-related diseases. •Kindlin-3–β2-integrin signaling in neutrophils is involved in regulation of both neutrophil recruitment and NET release.•Disrupting the crosstalk between kindlin-3 and β2-integrins in neutrophils with a blocking peptide preferentially attenuates NET release.