AB0178 Suppression of endoplasmic reticulum stress by 4-pba improves the manifestations of murine lupus through modulating regulatory t cells

Background Impaired function of regulatory T cells (Treg) contributes to the pathogenesis of systemic lupus erythematosus (SLE). It has been reported that the aberrant responses of T lymphocytes to endoplasmic reticulum (ER) stress in patients with SLE. Objectives In the present study, we investigated whether ER stress inhibition through 4-phenylbutyric acid (4-PBA) ameliorates lupus manifestation on experimental lupus model and the effect of ER stress inhibition by 4-PBA on the frequency and function of Treg. Methods Murine lupus model were induced with female BALB/c mice at 7 or 8 weeks of age through Toll-like receptor (TLR) agonist 7 treatment for 4 weeks. From the 8th week, the mice were treated with phosphate buffered saline (PBS), 4-PBA (500 mg/kg, three times weekly) and dexamethasone (1 mg/kg, once a day) for 4 weeks. The increment of body weight, spleen weight, anti-double-stranded DNA (anti-dsDNA) antibody titer, serum cytokine level and the pathology of glomerulonephritis were analysed at 12 weeks of age. The population of immune cellular subset including activated T, B lymphocyte and Treg and suppressive functions of Treg were measured. Results 4-PBA significantly decreased the level of anti-dsDNA antibodies, serum TNF-α in murine lupus model, and which were comparable with the efficacy of dexamethasone. A significant decrease in accumulation of immunoglobulin, glomerulonephritis score was also observed in 4-PBA-treated and dexamethasone-treated mice compared with vehicle-treated group. ER stress inhibition decreased the activated T and B lymphocytes population of splenocytes, but the population of Treg was not significantly different between vehicle group and 4-PBA group. However, there was the markedly enhanced suppressive capacity of Treg in 4-PBA-treated group. Conclusions The results suggest that ER stress inhibition attenuates disease activity in experimental model, especially in nephritis through improving the suppressive capacity of Treg. Thus, reduction of ER stress could be used as a beneficial therapeutic strategy in SLE. Disclosure of Interest None declared