2. Academic Validation
  3. Nexinhib20 Inhibits Neutrophil Adhesion and β2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction

Nexinhib20 Inhibits Neutrophil Adhesion and β2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction

  • J Immunol. 2022 Oct 15;209(8):1574-1585. doi: 10.4049/jimmunol.2101112.
Wei Liu 1,  Chunxia G Cronin 2,  Ziming Cao 1,  Chengliang Wang 1,  Jianbin Ruan 1,  Sunitha Pulikkot 1,  Alexxus Hall 1,  Hao Sun 3,  Alex Groisman 4,  Yunfeng Chen 5 6,  Anthony T Vella 1,  Liang Hu 7,  Bruce T Liang 8,  Zhichao Fan 9 10
Affiliations

Affiliations

  • 1 Department of Immunology, School of Medicine, UConn Health, Farmington, CT.
  • 2 Pat and Jim Calhoun Cardiology Center, School of Medicine, UConn Health, Farmington, CT.
  • 3 Department of Medicine, University of California San Diego, La Jolla, CA.
  • 4 Department of Physics, University of California San Diego, La Jolla, CA.
  • 5 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX.
  • 6 Department of Pathology, University of Texas Medical Branch, Galveston, TX.
  • 7 Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; and.
  • 8 Pat and Jim Calhoun Cardiology Center, School of Medicine, UConn Health, Farmington, CT; zfan@uchc.edu bliang@uchc.edu.
  • 9 Department of Immunology, School of Medicine, UConn Health, Farmington, CT; zfan@uchc.edu bliang@uchc.edu.
  • 10 Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA.
PMID: 36165184 DOI: 10.4049/jimmunol.2101112
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.

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