Galectin-9 mediates neutrophil capture and adhesion in a CD44 and β2 integrin-dependent manner.
Iqbal, Asif J Krautter, Franziska Blacksell, Isobel A Wright, Rachael D Austin-Williams, Shani N Voisin, Mathieu-Benoit Hussain, Mohammed T Law, Hannah L Niki, Toshiro Hirashima, Mitsuomi
Iqbal, Asif J
Krautter, Franziska
Blacksell, Isobel A
Wright, Rachael D
Austin-Williams, Shani N
Voisin, Mathieu-Benoit
Hussain, Mohammed T
Law, Hannah L
Niki, Toshiro
Hirashima, Mitsuomi
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2022-01
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Abstract
Neutrophil trafficking is a key component of the inflammatory response. Here, we have investigated the role of the immunomodulatory lectin Galectin-9 (Gal-9) on neutrophil recruitment. Our data indicate that Gal-9 is upregulated in the inflamed vasculature of RA synovial biopsies and report the release of Gal-9 into the extracellular environment following endothelial cell activation. siRNA knockdown of endothelial Gal-9 resulted in reduced neutrophil adhesion and neutrophil recruitment was significantly reduced in Gal-9 knockout mice in a model of zymosan-induced peritonitis. We also provide evidence for Gal-9 binding sites on human neutrophils; Gal-9 binding induced neutrophil activation (increased expression of β2 integrins and reduced expression of CD62L). Intra-vital microscopy confirmed a pro-recruitment role for Gal-9, with increased numbers of transmigrated neutrophils following Gal-9 administration. We studied the role of both soluble and immobilized Gal-9 on human neutrophil recruitment. Soluble Gal-9 significantly strengthened the interaction between neutrophils and the endothelium and inhibited neutrophil crawling on ICAM-1. When immobilized, Gal-9 functioned as an adhesion molecule and captured neutrophils from the flow. Neutrophils adherent to Gal-9 exhibited a spread/activated phenotype that was inhibited by CD18 and CD44 neutralizing antibodies, suggesting a role for these molecules in the pro-adhesive effects of Gal-9. Our data indicate that Gal-9 is expressed and released by the activated endothelium and functions both in soluble form and when immobilized as a neutrophil adhesion molecule. This study paves the way for further investigation of the role of Gal-9 in leukocyte recruitment in different inflammatory settings.
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Iqbal AJ, Krautter F, Blacksell IA, Wright RD, Austin-Williams SN, Voisin MB, Hussain MT, Law HL, Niki T, Hirashima M, Bombardieri M, Pitzalis C, Tiwari A, Nash GB, Norling LV, Cooper D. Galectin-9 mediates neutrophil capture and adhesion in a CD44 and β2 integrin-dependent manner. FASEB J. 2022 Jan;36(1):e22065. doi: 10.1096/fj.202100832R
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