Nexinhib20 Inhibits Neutrophil Adhesion and b2 Integrin Activation by Antagonizing Rac-1-Guanosine 59-Triphosphate Interaction

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 b2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8-induced b2 integrin-dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and b2 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.

Original languageEnglish (US)
Pages (from-to)1574-1585
Number of pages12
JournalJournal of Immunology
Volume209
Issue number8
DOIs
StatePublished - Oct 15 2022

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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