Die Rolle des GDF15 bei der Lupusnephritis
Zusammenfassung der Projektergebnisse
We had hypothesized a negative-regulatory role for GDF15 in the pathogenesis of systemic autoimmunity, i.e. murine lupus-like disease. The presented data support this concept as GDF15 acted as a suppressor of lymphoproliferation, B- and T-cell expansion, autoreactive plasma-cellmaturation, and consequently anti-DNA-directed autoantibody generation in the C57BL/6lpr/lpr model. Moreover, we found, that GDF15 suppresses type I interferon signature in lupus-prone mice. Yet, consistent with our previous data on negative regulators of TLR-signaling, an additional factor creating an autoimmune-convenient environment was required before this immunoregulatory role of Gdf15 came into play. Both, type I interferon and anti-dsDNA-autoantibody production, are hallmarks of systemic lupus or lupus-like disease. The type I interferon signature has been causally linked to SLE pathogenesis via (a) genetic gain-of-function variants-associated risk for disease, (b) induction of SLE-like phenotypes in interferon treated cancer patients, and (c) correlation of type I interferons with antinuclear antibodies (ANA)-titers, disease activity, and nephritis in lupus patients. Lastly, anifrolumab, an inhibitory human IgG1κ monoclonal antibody to type I interferon receptor subunit 1, showed promising results in the recent TULIP-2 trial performed in patients with active SLE. Gdf15- /- in lupus-prone C57BL/6lpr/lpr mice significantly enhanced the serologic IFNα and IFNγ production and enforced an inflammatory systemic cytokine profile of increased systemic TNFα and IL-12p70 serum levels. Our data highlight TLR-7/-9 hyperresponsiveness as a possible mechanism of the exaggerated type I signature in GDF15-deficient C57BL/6lpr/lpr mice. Although, plasmacytoid dendritic cells were considered the classical interferon producers in SLE, in the meantime macrophages have also been implicated in this process. Apart from exaggerated serologic auto-immune activity, GDF15-deficiency was associated with a mild nephritic phenotype in mice as evidenced by increased glomerular IgG deposits, mild hypercellularity, and reduced podocytes numbers as well as increased albumin creatinine ratios. However, we did not observe full-blown crescentic LN. One might argue, that 6 months of observation might have been too short to observe full-blown nephritis. In acute murine anti-GBM nephritis in C57BL/6 mice, GDF15- deficiency promoted CXCL10/CXCR3-dependent T cell infiltration and crescent formation. Although, GDF15 has a similar renal protective effect in all these models, its effect size varies between acute versus chronic inflammation. Thus, GDF15 suppresses lymphoproliferation, type I interferon-, and anti-DNA-autoantibody production in autoimmune-prone mice. Human data further indicates its involvement in human lupus nephritis.
Projektbezogene Publikationen (Auswahl)
- The Involvement of MicroRNAs in Modulation of Innate and Adaptive Immunity in Systemic Lupus Erythematosus and Lupus Nephritis. J Immunol Res. 2018 May 8;2018:4126106
Honarpisheh M, Köhler P, von Rauchhaupt E, Lech M
(Siehe online unter https://doi.org/10.1155/2018/4126106) - c-Rel gain in B cells drives germinal center reactions and autoantibody production. J Clin Invest. 2020 Jun 1;130(6):3270-3286
Kober-Hasslacher M, Oh-Strauß H, Kumar D, Soberon V, Diehl C, Lech M, Engleitner T, Katab E, Fernández-Sáiz V, Piontek G, Li H, Menze B, Ziegenhain C, Enard W, Rad R, Böttcher JP, Anders HJ, Rudelius M, Schmidt-Supprian M
(Siehe online unter https://doi.org/10.1172/jci124382) - Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice. Int J Mol Sci. 2020 Sep 23;21(19):6978
Moschovaki-Filippidou F, Steiger S, Lorenz G, Schmaderer C, Ribeiro A, von Rauchhaupt E, Cohen CD, Anders HJ, Lindenmeyer M, Lech M
(Siehe online unter https://doi.org/10.3390/ijms21196978) - Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation. Dis Model Mech. 2021 Mar 18;14(3):dmm047589
Dobosz E, Lorenz G, Ribeiro A, Würf V, Wadowska M, Kotlinowski J, Schmaderer C, Potempa J, Fu M, Koziel J, Lech M
(Siehe online unter https://doi.org/10.1242/dmm.047589) - GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus. J Innate Immun. 2022 Apr 20:1-17
Lorenz G, Ribeiro A, von Rauchhaupt E, Würf V, Schmaderer C, Cohen CD, Vohra T, Anders HJ, Lindenmeyer M, Lech M
(Siehe online unter https://doi.org/10.1159/000523991)
