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

Authors:

Deborah L Hodge, Cyril Berthet, Vincenzo Coppola, Wolfgang Kastenmüller, Matthew D Buschman, Paul M Schaughency, Hidekazu Shirota, Anthony J Scarzello, Jeff J Subleski, Miriam R Anver, John R Ortaldo, Fanching Lin, Della A Reynolds, Michael E Sanford, Philipp Kaldis, Lino Tessarollo, Dennis M Klinman, Howard A Young

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.

Ref: J Autoimmun. 2014 Sep;53:33-45. doi: 10.1016/j.jaut.2014.02.003. Epub 2014 Feb 28.

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