Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes

Abstract

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.

Differential regulation and correlation between galectin-9 and anti-CCP antibody (ACPA) in rheumatoid arthritis patients

“…More recently, Wiersma et al have reported that serum Gal-9 levels were elevated and correlated with disease activity (DAS-28) or smoking status in RA patient [26]. Our data are almost in line with these data.…”

“…Serum Gal-9 levels were elevated in RA patients with RA-related interstitial lung disease (RA-ILD); however, we could not find any associations between circulating Gal-9 and smoking status in our RA patients. Differences of ethnic and demographic data of the subjected RA patients may contribute to the differential result between our data and the reported data [26]. Further, large-scale investigations consisting of ethnic groups are needed to decide the mechanisms by which circulating Gal-9 is elevated in RA patients.…”

Differential Regulation and Correlation between Galectin-9 and anti-CCP antibody (ACPA) in Rheumatoid Arthritis Patients

“…Serum Gal-9 levels were elevated in RA patients with RA-related interstitial lung disease (RA-ILD), however, we could not find any associations between circulating Gal-9 and smoking status in our RA patients. Differences of ethnics and demographic data of the subjected RA patients may contribute to the differential result between our data and the reported data [26]. Further, large-scale investigations consisting of ethnic-groups are needed to decide the mechanisms by which circulating Gal-9 is elevated in RA patients.…”

Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19

“…Of these 84 genes, 16 genes were NETs associated genes ( Figure 5B; Table 3) (33-46) Of the 16 genes, LGALS9, HCK, LCP1, CEACAM1 were involved in the cytokine-mediated signaling pathway. S100A8, LGALS9, and CTSC were involved in regulation of apoptotic signal by enrichment annotation from the Metascape tool ( Figure 5B; Table 3) (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”