GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus

Lorenz, Georg; Ribeiro, Andrea; Rauchhaupt, Ekatharina von; Wuerf, Vivian; Schmaderer, Christoph; Cohen, Clemens D.; Vohra, Twinkle; Anders, Hans-Joachim; Lindenmeyer, Maja und Lech, Maciej (2022): GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus. In: Journal of Innate Immunity, Bd. 14, Nr. 6: S. 673-689

Abstract

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-beta superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis. Still, its role in systemic autoimmune disease remains elusive. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6(lpr/lpr)) backgrounds. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. Splenocytes of phenotypically overall-normal Gdf15-/- C57BL/6 and lupus-prone C57BL/6(lpr/lpr) mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1662-811X
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892