Inflammatory factor-mediated miR-155/SOCS1 signaling axis leads to Treg impairment in systemic lupus erythematosus

Abstract

Inflammatory factors in systemic lupus erythematosus (SLE) trigger a signaling cascade in regulatory T cells (Tregs), leading to their functional impairment. This process involves the upregulation of miR-155 and downregulation of SOCS1, with a concomitant decrease in Foxp3 expression and an increased NF-κB activity. These changes compromise Treg stability and function, contributing to SLE progression. Notably, inhibition of miR-155 shows promise in rescuing Treg function and potentially alleviating SLE symptoms, highlighting a novel therapeutic approach for managing this autoimmune disorder. • Tregs from SLE patients and SLE-induced mice exhibited a downregulation of SOCS1 and an upregulation of miR-155. • In Tregs stimulated by inflammatory cytokines, Nuclear factor kappa B (NF-κB) signaling activation was required for the change of SOCS1 and miR-155 expression. • miR-155 served as a negative regulator to dampen SOCS1 expression in inflammation-stimulated Tregs. • The transfection of miR-155 mimic impaired the suppressive function and differentiation of Tregs through targeting SOCS1. • miR-155 inhibition improved Treg function under inflammatory stimulation and alleviated SLE conditions in the mouse model. Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with the decrease and functional impairment of regulatory T cells (Tregs). In the current study, we explored the interplay of miR-155 and suppressor of cytokine signaling 1 (SOCS1) in regulating Treg function and stability in SLE. Clinical samples from healthy subjects and SLE patients were collected, and a mouse model of SLE was established to profile the expression pattern of miR-155 and SCOS1 in Tregs. Tregs isolated from mouse spleen were stimulated by inflammatory cytokines to confirm involvement of miR-155/SOCS1 axis in dictating Treg stability and function. We also administrated synthetic miR-155 inhibitor in SLE animal model to evaluate the potential effect on rescuing Treg function and alleviating SLE progression. Tregs from SLE patients and SLE-induced mice exhibited a downregulation of SOCS1 and an upregulation of miR-155. In Tregs stimulated by inflammatory cytokines, Nuclear factor kappa B (NF-κB) signaling activation was required for the change of SOCS1 and miR-155 expression. miR-155 served as a negative regulator to dampen SOCS1 expression in inflammation-stimulated Tregs. The transfection of miR-155 mimic impaired the suppressive function and differentiation of Tregs through targeting SOCS1. In contrast, miR-155 inhibition improved Treg function under inflammatory stimulation and alleviated SLE conditions in the mouse model. Inflammation-induced miR-155 impairs Treg stability and function in SLE through decreasing SOCS1 expression. Targeting miR-155 might be developed as an intervention to mitigate SLE conditions.

Topics & Concepts