Heterozygous Gnaq deficiency enhances Ifi202b/IFI16 and NF-κB activation in endothelial cells and exacerbates lupus nephritis pathology.

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), exhibits significant heterogeneity. Recent evidence suggests that non-immune factors contribute to end-organ damage, challenging the traditional view of LN solely arising from immune dysregulation. To investigate this, we employed autoimmune-prone mice receiving intraperitoneal pristane injections. Bone marrow transfer (BMT) distinguished the roles of immune versus non-immune cells. We observed that: (1) BMT from wild-type (WT) mice to recipients resulted in severe proteinuria and diffuse proliferative nephritis after pristane exposure; (2) GNAQ knockdown increased the expression of IFI16/Ifi202b and activated the NF-κB pathway in endothelial cells; and (3) increased IFI16 expression in human kidney biopsies correlated with proliferative LN. Taken together, these findings suggest that GNAQ acts as an inflammatory regulator in kidney endothelial cells via the IFI16/NF-κB pathway, potentially linking it to the development of LN in humans.