Arabinogalactan from Cynanchum atratum induces tolerogenic dendritic cells in gut to restrain autoimmune response and alleviate collagen-induced arthritis in mice

Abstract

Background

Rheumatoid arthritis (RA) is an autoimmune disease characterized by multiple joints lesions. Tolerogenic dendritic cells (tolDCs) play crucial roles in maintaining immune homeostasis. The immunomodulatory activity of plant-derived arabinogalactan (AGs) has been well investigated, however, whether AGs could suppress autoimmune responses by inducing tolDCs is remain unclear.

Design

Collagen-induced arthritis (CIA, a mouse model of RA) mice were utilized to ascertain the role of AGs (obtained from Cynanchum atratum) in autoimmune responses. An antibiotic cocktail was administered to eliminate gut microbiota. Germ-free (GF) and Toll-like receptor 2 (TLR2) knockout mice were used to determine the function of AGs in intestinal immune cells.

Results

The oral administration of dietary AGs substantially reduced the severity of CIA and rebalanced the ratio of regulatory T cells (Tregs) to T helper 17 (Th17) cells. Although the antibiotic cocktail depleted the mice's gut microbiota, AGs had a therapeutic effect on their CIA. AGs restored Treg/Th17 homeostasis by inducing CD103⁺ tolDCs, regardless of the gut microbiota of the GF mice. Coculture experiments confirmed that AGs induced tolDCs and transforming growth factor β (TGF-β) secretion, leading to Treg amplification. RNA sequencing and TLR2 knockout experiments revealed that AGs induced tolDCs through a TLR2-mediated mechanism. Preventive interventions with AGs established a tolerogenic intestinal immune microenvironment, which delayed the onset and progression of CIA. AGs functioned synergistically with tofacitinib, a JAK inhibitor, to effectively restore Treg/Th17 balance and alleviate CIA.

Conclusion

This study introduces a novel microbiota-independent mechanism through which soluble dietary AGs inhibit systemic autoimmune responses. Our findings provide insights into the supplementation of dietary AGs in patients with preclinical or progressive RA.