Nexinhib20 Inhibits Neutrophil Adhesion and β 2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction.
Wei LiuChunxia G CroninZiming CaoChengliang WangJianbin RuanSunitha PulikkotAlexxus HallHao SunAlex GroismanYunfeng ChenAnthony T VellaLiang HuBruce T LiangZhichao FanPublished in: Journal of immunology (Baltimore, Md. : 1950) (2022)
Neutrophils are critical for mediating inflammatory responses. Inhibiting neutrophil recruitment is an attractive approach for preventing inflammatory injuries, including myocardial ischemia-reperfusion (I/R) injury, which exacerbates cardiomyocyte death after primary percutaneous coronary intervention in acute myocardial infarction. In this study, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits not only exocytosis but also neutrophil adhesion by limiting β 2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8-induced β 2 integrin-dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β 2 integrin activation after IL-8 stimulation. Western blots of Ras-related C3 botulinum toxin substrate 1 (Rac-1)-GTP pull-down assays confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. An in vitro competition assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.
Keyphrases
- acute myocardial infarction
- cell migration
- percutaneous coronary intervention
- left ventricular
- high throughput
- mouse model
- cell adhesion
- flow cytometry
- signaling pathway
- botulinum toxin
- endothelial cells
- coronary artery disease
- heart failure
- south africa
- high glucose
- st segment elevation myocardial infarction
- biofilm formation
- escherichia coli
- drug induced
- angiotensin ii
- atrial fibrillation
- single cell
- brain injury
- coronary artery bypass grafting
- transcription factor
- subarachnoid hemorrhage
- binding protein
- amino acid
- blood brain barrier
- staphylococcus aureus
- diabetic rats
- antiplatelet therapy
- stress induced
- cerebral ischemia