Mesenchymal Stem Cells Control Complement C5 Activation by Factor H in Lupus Nephritis

Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE) caused by uncontrolled activation of the complement system. Mesenchymal stem cells (MSCs) exhibit clinical efficacy for severe LN in our previous studies, but the underlying mechanisms of MSCs regulating complement activation remain largely unknown. Here we show that significantly elevated C5a and C5b-9 were found in patients with LN, which were notably correlated with proteinuria and different renal pathological indexes of LN. MSCs suppressed systemic and intrarenal activation of C5, increased the plasma levels of factor H (FH), and ameliorated renal disease in lupus mice. Importantly, MSCs transplantation up-regulated the decreased FH in patients with LN. Mechanistically, interferon-α enhanced the secretion of FH by MSCs. These data demonstrate that MSCs inhibit the activation of pathogenic C5 via up-regulation of FH, which improves our understanding of the immunomodulatory mechanisms of MSCs in the treatment of lupus nephritis. [Display omitted] •Extensively activated C5 might contribute to the progression of lupus nephritis.•MSCs ameliorated renal disease in lupus mice through inhibiting systemic and intrarenal activation of C5.•MSCs increased plasma FH in lupus mice and patients, while interferon-α enhanced the secretion of FH from MSCs. Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE). Here we show that obviously increased C5a and C5b-9 were found in patients with LN, and which were notably correlated with some clinical parameters of LN. Mesenchymal stem cells (MSCs) reduced renal disease in lupus mice through factor H (FH), one of complement regulatory proteins, suppressing C5 over-activation. Interestingly, enhanced secretion of FH from MSCs could be induced by interferon-α. The findings would expand our understanding of the complement regulatory mechanisms of MSCs in treating lupus nephritis.