Amelioration of bleomycin-induced pulmonary fibrosis via TGF-β-induced Smad and non-Smad signaling pathways in galectin-9-deficient mice and fibroblast cells

Abstract

Background: Galectin-9 is a β-galactoside-binding protein with two carbohydrate recognition domains. Recent studies have revealed that galectin-9 regulates cellular biological reactions and plays a pivotal role in fibrosis. The aim of this study was to determine the role of galectin-9 in the pathogenesis of bleomycin-induced systemic sclerosis (SSc). Methods: Human galectin-9 levels in the serum of patients with SSc and mouse sera galectin-9 levels were measured by a Bio-Plex immunoassay and enzyme-linked immunosorbent assay. Lung fibrosis was induced using bleomycin in galectin-9 wild-type and knockout mice. The effects of galectin-9 on the fibrosis markers and signaling molecules in the mouse lung tissues and primary lung fibroblast cells were assessed with western blotting and quantitative polymerase chain reaction. Results: Galectin-9 levels in the serum were significantly higher (9-fold) in patients compared to those of healthy individuals. Galectin-9 deficiency in mice prominently ameliorated epithelial proliferation, collagen I accumulation, and α-smooth muscle actin expression. In addition, the galectin-9 knockout mice showed reduced protein expression levels of fibrosis markers such as Smad2/3, connective tissue growth factor, and endothelin-1. Differences between the wild-type and knockout groups were also observed in the AKT, mitogen-activated protein kinase, and c-Jun N-terminal kinase signaling pathways. Galectin-9 deficiency decreased the signal activation induced by transforming growth factor-beta in mouse primary fibroblasts, which plays a critical role in fibroblast activation and aberrant catabolism of the extracellular matrix. Conclusions: Our findings suggest that lack of galectin-9 protects against bleomycin-induced SSc. Moreover, galectin-9 might be involved in regulating the progression of fibrosis in multiple pathways.

Proteomics reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients

“…The inflammation markers LGALS9 ( Signaling by Interleukins , Interleukin - 2 family signaling ) and SIRPB1 ( Neutrophil degranulation , Signal regulatory protein family interactions , DAP12 interactions ) were significantly upregulated in both acute phases compared to Ctrl - noninfl , next to LRIG1, not represented in any regulated pathway. Interestingly, regulated proteins such as LGALS9 or SIRPB1 hold matrix remodeling capacities next to immune functions [36] , [37] .…”

Proteome reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients

“…The inflammation markers LGALS9 (Signaling by Interleukins , Interleukin-2 family signaling ) and SIRPB1 ( Neutrophil degranulation , Signal regulatory protein family interactions , DAP12 interactions ) were significantly upregulated in both acute phases compared to Ctrl-noninfl , next to LRIG1, not represented in any regulated pathway. Interestingly, regulated proteins such as LGALS9 or SIRPB1 hold matrix remodeling capacities next to immune functions (Hsu et al , 2020; Chen et al , 2019b).…”

Possible important roles of galectins in the healing of human fetal membranes

“…Epithelial cell proliferation is significantly decreased, collagen-I accumulation is decreased, and alpha smooth muscle actin expression is downregulated in galectin-9-deficient mice. Galectin-9 promotes extracellular matrix synthesis and collagen accumulation via TGF-β-induced MAPK/ERK, TAK1/JNK, and PI3K/AKT signaling pathways ( 66 ). Galectin-8 stimulates TGF-β1 via β1-integrin/FAK pathways to enhance type I collagen, fibronectin FN and connective tissue growth factor CTGF protein levels in human gingival fibroblasts ( 67 ).…”