Deficiency of the type I interferon receptor protects mice from experimental lupus

Abstract

Objective. Systemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN-I)-stimulated genes (ISGs). The role of IFN-I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN-I signaling in the pathogenesis of murine lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD).Methods. IFN-I receptor-deficient (IFNAR ؊/؊ ) 129Sv mice and wild-type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real-time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme-linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence.Results. Increased ISG expression was observed in the peripheral blood of TMPD-treated WT mice, but not in the peripheral blood of TMPD-treated IFNAR ؊/؊ mice. TMPD did not induce lupus-specific autoantibodies (anti-RNP, anti-Sm, anti-double-stranded DNA) in IFNAR ؊/؊ mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR ؊/؊ mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD-treated WT controls. The clinical and serologic manifestations observed in TMPD-treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus-specific autoantibodies and nephritis in humans.Conclusion. Similar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD-induced lupus. This lupus model is the first animal model shown to recapitulate the "interferon signature" in peripheral blood.

A Novel Type I IFN-Producing Cell Subset in Murine Lupus

“…Disruption of IFN-I signaling completely abrogates the development of kidney disease and the onset of autoantibody production (9). In this study, we show that Ly6C high monocytes are a major source of IFN-I in the TMPD model of lupus.…”

“…It is noteworthy that although IFN-I is essential to TMPD-induced lupus (9), other factors such as IL-12 and IFN-␥ play important roles because autoantibody production and kidney disease development are reduced in deficient mice (32,33).…”

“…This murine model is at present the only one reported to have the "IFN signature". IFN-I signaling is critically required in this model as shown by the absence of lupus autoantibodies and kidney disease in IFN-I receptor ␣-chain-deficient (IFNAR Ϫ/Ϫ ) mice) (9). The source of the excess IFN-I, however, has not been examined.…”

Melanoma Differentiation-Associated Gene 5 Regulates the Expression of a Chemokine CXCL10 in Human Mesangial Cells: Implications for Chronic Inflammatory Renal Diseases

“…IFN-β has anti-viral and anti-tumor properties and is involved in the pathogenesis of autoimmune diseases such as lupus nephritis (Nacionales et al 2007). Viral RNA and DNA can activate IFN signaling in glomerular mesangial cells and endothelial cells.…”

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

“…Indeed, extensive animal and human studies have revealed a crucial role for type I IFN in the initiation and perpetuation of disease, and components of the IFN system, including transcription factors, are now putative drug targets and biomarkers in the treatment of SLE. Indeed type I IFN plays a critical role in the immunopathogenesis of SLE, since IFNAR-deleted mice fail to develop disease [135,136].…”