-
Views
-
Cite
Cite
Wei Liu, Chunxia G Cronin, Ziming Cao, Chengliang Wang, Jianbin Ruan, Sunitha Pulikkot, Alexxus Hall, Hao Sun, Alex Groisman, Yunfeng Chen, Anthony T Vella, Liang Hu, Bruce T Liang, Zhichao Fan, Nexinhib20 Inhibits Neutrophil Adhesion and β2 Integrin Activation by Antagonizing Rac-1–Guanosine 5′-Triphosphate Interaction, The Journal of Immunology, Volume 209, Issue 8, October 2022, Pages 1574–1585, https://doi.org/10.4049/jimmunol.2101112
- Share Icon Share
Abstract
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 β2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8–induced β2 integrin–dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β2 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.