期刊
BLOOD
卷 126, 期 3, 页码 373-377出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-03-636720
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类别
资金
- Blood Center Research Foundation of the BloodCenter of Wisconsin
- National Natural Science Foundation of China [81270579, 31370748]
- Medical College of Wisconsin Cancer Center/Wisconsin Breast Cancer Showhouse
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 alpha IIb beta 3 in platelets. Here, using K3KI mice, we functionally evaluate the crosstalk between kindlin-3 and beta(2)-integrins in neutrophils. Although the kindlin-3 mutant in K3KI neutrophils is normally expressed, its binding ability to beta(2)-integrins in neutrophils is disabled. In vitro and in vivo analyses disclose that beta(2)-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 beta(2) cytoplasmic tail that can inhibit the interaction between kindlin-3 and beta(2)-inegrins significantly jeopardizes NET release without affecting neutrophil adhesion and recruitment under the experimental conditions. These findings suggest that crosstalk between kindlin-3 and beta(2)-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.
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