Abstract
Gout is caused by depositing monosodium urate (MSU) crystals within the articular area. The infiltration of neutrophils and monocytes drives the initial inflammatory response followed by lymphocytes. Interestingly, emerging evidence supports the view that in situ imbalance of T helper 17 cells (Th17)/regulatory T cells (Treg) impacts the subsequent damage to target tissues. Galectin-9 (Gal-9) is a modulator of innate and adaptive immunity with both pro- and anti-inflammatory functions, dependent upon its expression and cellular location. However, the specific cellular and molecular mechanisms by which Gal-9 modulates the inflammatory response in the onset and progression of gouty arthritis has yet to be elucidated. In this study, we sought to comprehensively characterise the functional role of exogenous Gal-9 in an in vivo model of MSU crystal-induced gouty inflammation by monitoring in situ neutrophils, monocytes and Th17/Treg recruited phenotypes and related cyto-chemokines profile. Treatment with Gal-9 revealed a dose-dependent reduction in joint inflammation scores, knee joint oedema and expression of different pro-inflammatory cyto-chemokines. Furthermore, flow cytometry analysis highlighted a significant modulation of infiltrating inflammatory monocytes (CD11b+/CD115+/LY6-Chi) and Th17 (CD4+/IL-17+)/Treg (CD4+/CD25+/FOXP-3+) cells following Gal-9 treatment. Collectively the results presented in this study indicate that the administration of Gal-9 could provide a new therapeutic strategy for preventing tissue damage in gouty arthritic inflammation and, possibly, in other inflammatory-based diseases.
Highlights
Inflammation is broadly defined as a host response to homeostatic imbalance triggered by conditions such as infection, tissue injury and noxious stimuli, including exposure to chemicals or radiation [1]
To investigate the potential anti-inflammatory effect of Gal-9, we used a mouse model in which monosodium urate crystals (MSU) crystals were injected into knee joints, to mimic the etiologic cause of human gouty inflammation [33]
MSU crystals injection (200μg/20μl) evoked an intense and robust joint inflammatory score that was dosedependently attenuated by Gal-9 (1-9μg/20μl) administration (Supplementary Figure 1A), with maximum inhibition observed at a dose of 9μg/20μl (Figure 1A)
Summary
Inflammation is broadly defined as a host response to homeostatic imbalance triggered by conditions such as infection, tissue injury and noxious stimuli, including exposure to chemicals or radiation [1]. One of the preliminary steps in the onset of inflammation is the recruitment of leukocytes to the site of injury or infection [2]. The infiltration of innate immune cells drives the initial inflammatory response followed by lymphocytes [3, 4]. Emerging evidence supports the view that, in different inflammatory-based responses such as gouty arthritis, systemic imbalance of Th17/Treg induces their infiltration in situ and related damage to target tissues [5, 6]. The Th17/Treg balance provides a basis for understanding the immunological mechanisms that induce and regulate autoimmune and some inflammatory-based diseases [13]
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