IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice

Abstract

We generated a mouse model with a 162 nt AU-rich element (ARE) region deletion in the 3′ untranslated region (3′UTR) of the interferon-gamma (IFN-γ) gene that results in chronic circulating serum IFN-γ levels. Mice homozygous for the ARE deletion (ARE-Del) −/− present both serologic and cellular abnormalities typical of patients with systemic lupus erythematosus (SLE). ARE-Del−/− mice display increased numbers of pDCs in bone marrow and spleen. Addition of IFN-γ to Flt3-ligand (Flt3L) treated in vitro bone marrow cultures results in a 2-fold increase in pDCs with concurrent increases in IRF8 expression. Marginal zone B (MZB) cells and marginal zone macrophages (MZMs) are absent in ARE-Del−/− mice. ARE-Del+/− mice retain both MZB cells and MZMs and develop no or mild autoimmunity. However, low dose clodronate treatment in ARE-Del+/− mice specifically eliminates MZMs and promotes anti-DNA antibody development and glomerulonephritis. Our findings demonstrate the consequences of a chronic IFN-γ milieu on B220+ cell types and in particular the impact of MZB cell loss on MZM function in autoimmunity. Furthermore, similarities between disease states in ARE-Del−/− mice and SLE patients suggest that IFN-γ may not only be a product of SLE but may be critical for disease onset and progression.

Current prospects of type II interferon γ signaling and autoimmunity

“…To address this issue, our laboratory designed a mouse model carrying deletion of the ifng 3Ј-untranslated region adenylate uridylate-rich element (ARE). The persistent serum levels of IFN␥, due to increased stability of mRNA, result in gradual establishment of SLE-like autoimmunity (80). More importantly, we have provided evidence that heterozygous ARE-del mice share similar levels of autoantibodies and demonstrate a histological score of tissue damage in target organs like that seen in homozygous ARE-del mice that express twice the systemic IFN␥ levels (80,81).…”

“…The persistent serum levels of IFN␥, due to increased stability of mRNA, result in gradual establishment of SLE-like autoimmunity (80). More importantly, we have provided evidence that heterozygous ARE-del mice share similar levels of autoantibodies and demonstrate a histological score of tissue damage in target organs like that seen in homozygous ARE-del mice that express twice the systemic IFN␥ levels (80,81). This evidence suggests the existence of a threshold level of IFN␥ that, when crossed, results in a more severe pathology.…”

Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus

“…High IFN-g levels are linked to SLE onset [62], as exemplified recently in a murine model, where chronic circulating levels of this cytokine (ARE-Del mice) trigger a SLE-like syndrome [63]. In this model, NK cells produced more IFN-g compared with controls, both in basal conditions and after stimulation by IL-12 [63]. Little is known about their secretion of other cytokines in SLE, although NK cells from SLE patients produce lower levels of CCL4, which induces IFN-a production [64].…”

“…Indeed, NK cells from patients with active SLE produce higher IFN-g levels than healthy controls after stimulation by IL-12 + IL-18 (2 cytokines that induce IFN-g expression [61]) or by PMA + ionomycin [46,48]. High IFN-g levels are linked to SLE onset [62], as exemplified recently in a murine model, where chronic circulating levels of this cytokine (ARE-Del mice) trigger a SLE-like syndrome [63]. In this model, NK cells produced more IFN-g compared with controls, both in basal conditions and after stimulation by IL-12 [63].…”

T-cells require post-transcriptional regulation for accurate immune responses

“…Mice lacking TTP develop a complex inflammatory syndrome that is associated with a prolonged TNF-α mRNA halflife and elevated levels of circulating TNF-α [26]. Likewise, deletion of AREs within the 3 -UTR of TNF-α and IFN-γ results in chronic protein production that causes spontaneous development of chronic inflammatory arthritis, Crohn's-like inflammatory bowel disease, Lupus-like disease and aplastic anaemia [27][28][29].…”