title: Interaction of kindlin-3 and β2-integrins differentially regulates neutrophil recruitment and NET release in mice.
abstract: 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.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Collaborative Research Program for Cell Adhesion Molecules, Shanghai University School of Life Sciences, Shanghai, China;
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China; and.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Cai
authors.affiliation: Collaborative Research Program for Cell Adhesion Molecules, Shanghai University School of Life Sciences, Shanghai, China;
authors.forename: Juan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Biochemistry, Medical College of Milwaukee, Milwaukee, WI.
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: White
authors.affiliation: Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China; and.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Chen
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Collaborative Research Program for Cell Adhesion Molecules, Shanghai University School of Life Sciences, Shanghai, China; Department of Biochemistry, Medical College of Milwaukee, Milwaukee, WI.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Ma
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; C527818:kindlin-3 protein, mouse