Disabled-2 overexpression mediates immune suppression in systemic lupus erythematosus by modulating Treg/Th17 cell differentiation

Systemic lupus erythematosus (SLE) is an autoimmune disorder. T helper 17 (Th17) and regulatory T (Treg) cells play key roles in SLE progression. Disabled-2 (DAB2) exhibits immunomodulatory effects in inflammatory diseases. However, the role of DAB2 in SLE and the precise mechanisms remain unknown. Here, a decreased DAB2 expression and an increased miR-448-3p level were observed in peripheral blood mononuclear cells (PBMCs) from SLE patients. DAB2 level was negatively correlated with SLE Disease Activity Index (SLEDAI), suggesting a functional correlation between DAB2 and SLE. To test this, we used 8-week-old MRL/lpr mice and treated them with lentivirus-mediated DAB2 (LV-DAB2) or its negative control (LV-NC). LV-DAB2 treatment increased DAB2 expression and reduced serum immunoglobulin G (IgG) and anti-dsDNA IgG levels. DAB2 upregulation alleviated splenomegaly and lymphadenopathy and SLE-related organ damage. Moreover, DAB2 enhanced the percentage of CD25⁺ Foxp3⁺ Treg cells, but reduced Th17 cell frequency in lupus, along with the reduction in tumour necrosis factor α (TNF-α), interleukin (IL)-6 (IL-6) and IL-17A levels, and the elevation in IL-10. In vitro, naive CD4⁺ T cells isolated from MRL/lpr mice were polarized into Th17 or Treg phenotypes and treated with lentivirus. LV-DAB2 treatment downregulated IL-17A expression and inhibited the generation of CD4⁺ IL-17A⁺ Th17 cells. DAB2 triggered the production of IL-10 and the activation of Treg cells. Furthermore, DAB2 was verified as a direct target for miR-448-3p. MiR-448-3p overexpression cancelled the promoting effect of DAB2 on Treg cell differentiation. Taken together, DAB2 exerts an immunosuppressive effect on SLE through promoting Treg cell activation and inhibiting Th17 cell differentiation, which may be modulated by miR-448-3p.

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