Abstract
Zinc is a trace element that is essential for immune responses. Therefore, changes in cellular zinc levels in specific immune cells may influence inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). However, the regulation of zinc mobilization in immune cells and its role in the pathogenesis of RA are not fully understood. Thus, we investigated the roles of zinc transporters in RA pathogenesis. We demonstrated that ZIP8 was specifically upregulated in CD4+ T cells that infiltrated the inflamed joint and that ZIP8 deficiency in CD4+ T cells abrogated collagen-induced arthritis. ZIP8 deficiency dramatically affected zinc influx in effector T cells and profoundly reduced T cell receptor (TCR)-mediated signaling, including NF-κB and MAPK signaling, which are pathways that are involved in T helper (Th) 17 cell differentiation. Taken together, our findings suggest that ZIP8 depletion in CD4+ T cells attenuates TCR signaling due to insufficient cellular zinc, thereby reducing the function of effector CD4+ T cells, including Th17 cells. Our results also suggest that targeting ZIP8 may be a useful strategy to inhibit RA development and pathogenesis.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects joint tissues
The values are presented as mean ± SEM, and the χ2 test was used to analyze the incidence of collagen-induced arthritis (CIA) on day 39 (a); the values are presented as mean ± 95% confidence interval (95% CI) and were assessed with the Mann-Whitney U test (b, c); the values are presented as mean ± SEM and were assessed with analysis of variance (ANOVA) followed by Bonferroni’s post hoc comparison (e, f). *P < 0.05, **P < 0.005, ***P < 0.0005. ns: not significant
It has not yet been elucidated whether cell typespecific and transporter-specific zinc mobilization are involved in RA pathogenesis
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects joint tissues. This disease is characterized by synovial inflammation, cartilage destruction, and bone erosion[1,2]. The human leukocyte antigen allele HLA-DRB1 in the major histocompatibility locus was the first RA risk locus identified; this allele regulates disease progression by affecting the T cell receptor (TCR) repertoire and/or the presentation of antigens to self-reactive T cells[3,4]. During synovial inflammation in RA pathogenesis, various leukocytes infiltrate the synovial compartment via the increased expression of adhesion molecules and chemokines in the endothelium, leading to the production of large amounts of chemokines and proinflammatory cytokines in inflamed synovial tissues[2]. Subsequent to the discovery of interleukin (IL)-17-producing CD4+ T cells in the RA synovium, studies using animal
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