Therapeutic Effects of a Synthetic Glabridin Derivative on Th17/ B cell Immune Regulation and Salivary gland Regeneration in Experimental Sjögren’s Syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease in which inflammatory cells infiltrate the exocrine glands, reducing glandular secretory function and ultimately resulting in keratoconjunctivitis sicca (dry eyes) and xerostomia (oral dryness). Cardiovascular risk factors are more prevalent in patients with SS than in healthy controls; patients with SS and metabolic syndrome also have higher leptin and inflammatory cytokine levels. In this study, we investigated the effects of HGR4113, a structural analog of glabridin that promotes mitochondrial function and is in clinical trials for obesity treatment, on the development of Sjögren’s syndrome in non-obese diabetic NOD/ShiLtJ (NOD) mice. HGR4113 inhibited IL-17 production by regulating STAT3 activity and the metabolic profile of splenic CD4 + T cells; it also increased the frequency of IL-10-producing regulatory B cells and decreased immunoglobulin production. Oral administration of HGR4113 (100 mg/kg) improved salivary flow rate, reduced lymphocyte infiltration, and lowered inflammatory cytokine levels in the salivary glands of NOD mice. HGR4113 also decreased the frequencies of splenic IL-17-producing T and B cells, germinal center B cells, and plasma cells ex vivo in NOD mice. Additionally, organoid formation from salivary gland stem cells of HGR4113-treated NOD mice increased, as did the levels of E-cadherin-14, aquaporin-5, α-SMA, and cytokeratin-14. Finally, treatment with HGR4113 promoted salivary gland organoid formation in vitro . HGR4113 improves salivary gland hypofunction by inhibiting lymphocyte infiltration and inflammation in the salivary glands and restoring damaged salivary tissue in SS-like NOD mice.