Galectin‐9 mediates neutrophil capture and adhesion in a CD44 and β2 integrin‐dependent manner

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.

Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner

“…Further studies with larger sample sizes are needed to confirm our results and to define changes in middle-aged and perimenopausal groups, also at high risk for infection in the US [ 82 ]. Finally, we have described a number of factors that are modified in a high-SCFA environment that could be relevant for inflammation and antiviral defense; however, additional factors and underlying mechanisms for the described changes remain to be investigated, such as, for example, the potential role of galectin-9 modifications in inflammatory cytokine/chemokine release and neutrophil recruitment [ 83 , 84 , 85 , 86 ].…”

Plasma proteome responses in zebrafish following λ-carrageenan-Induced inflammation are mediated by PMN leukocytes and correlate highly with their human counterparts

“…Some critical examples of these proteins are Gelsolin, Galectin, Ezrin, and Elastase that we found in the ZF-treated plasma proteome. Gelsolin and Galectin play an immunomodulatory role in regulating the general PMN leukocytes movement, particularly neutrophil recruitment ( 94 , 95 ). At the same time, Ezrin and Elastase regulate cell adhesion by connecting critical membrane adhesion receptors, such as ICAM-I and VCAM, to the keratin or actin-based cytoskeleton in epithelial and endothelial tissues ( 96 , 97 ).…”

Galectin-9/Tim-3 pathway mediates dopaminergic neurodegeneration in MPTP-induced mouse model of Parkinson’s disease

“…As a member of the galectin family, Gal-9 is involved in various physiological and pathological processes, including cell adhesion ( Eckardt et al, 2020 ; Krautter and Iqbal, 2021 ; Iqbal et al, 2022 ; Pally et al, 2022 ), migration ( Mansour et al, 2022 ), differentiation ( Fan et al, 2018 ; Bertino et al, 2019 ), angiogenesis ( Aanhane et al, 2018 ; Hill et al, 2021 ), and immunomodulation ( Fan et al, 2018 ; Wiersma et al, 2019 ; Yan et al, 2022 ). In the central nervous system, Gal-9 is mainly expressed in microglia ( Steelman et al, 2013 ).…”