Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3

Abstract

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by a spectrum of autoantibodies that target multiple cellular components. Glomerulonephritis is a major cause of morbidity in patients with SLE. Little is known about the pathogenesis of SLE renal damage and compromised renal function. Activation of both Stat1 and Stat3 has been reported in lupus and lupus nephritis. The reciprocal activation of these two transcription factors may have a major impact on renal inflammation. To study the role of Stat1 in a lupus model, we induced lupus-like chronic graft-versus-host disease (cGVHD) in Stat1-KO and in WT mice by intraperitoneal injection of class II-disparate bm12 splenocytes. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4. In contrast, Stat1-KO hosts exhibited a prolonged and significant increase of anti-dsDNA autoantibody responses compared to WT mice (week 4 to week 8). Increased autoantibody titers were accompanied by increased proteinuria and mortality in the cGVHD host mice lacking Stat1. Further analysis revealed expression and activation of Stat3 in the glomeruli of Stat1-KO host mice but not WT mice with cGVHD. Glomerular Stat3 activity in the Stat1-KO mice was associated with increased IL-6 and IFN-γ secretion and macrophage infiltration. Interactions between Stat1 and Stat3 thus appear to be crucial in determining the severity of lupus-like disease in the cGVHD model.

Opposing Roles of Tyrosine Kinase Receptors Mer and Axl Determine Clinical Outcomes in Experimental Immune-Mediated Nephritis

“…Stat3 activation was associated with SOCS3 down regulation in the kidneys of the same mice. Consistent with previous findings, data shown here suggest a negative regulatory role for SOCS3 on Stat3 activation (35, 36). In addition, our previous data showed that Stat3 activation in the kidney was associated with severe nephritis in chronic graft-versus-host disease (cGVHD) (35).…”

“…An additional consequence of caspase1 activation in macrophages is rapid and caspase-1-dependent cell death (43). Increased IL-1 secretion and enhanced apoptotic cell death were reported previously in the kidneys of Mer-KO mice injected with NTS (35). Strikingly, Caspase1 activation (cleavage) was only observed in the kidneys of the nephritic mice lacking the Mer receptor, indicating a Mer-dependent caspase1 inhibition.…”

“…Enhanced Stat3 phosphorylation was associated with SOCS3 down regulation, which reinforces the inhibitory role of SOCS3 in Stat3 activation. Similarly, enhanced Stat3 phosphorylation was observed in the kidneys of Stat1-KO mice when lupus-like cGVHD was induced (35). Stat3 activation in the kidneys of nephritic Mer-KO mice was probably due to a negative feedback from Mer-mediated Stat1 activation, as Stat1 and Stat3 reciprocally regulate each other, and play opposite roles in several aspects of inflammation (41).…”

Regulation of Lupus Nephritis by Stat3

“…To study the role of Stat1 in a lupus model, we induced SLE-like chronic graft-versus-host disease (cGVHD) in Stat1-KO and in WT mice by intraperitoneal injection of class II-disparate bm12 splenocytes [6]. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4.…”

“…Enhanced expression and activation of Stat3 were observed in the glomeruli of Stat1-KO host mice but not WT mice with cGVHD. Interactions between Stat1 and Stat3 thus appear to be crucial in determining the severity of lupus-like disease in the cGVHD model [6].…”