Die Rolle des NLRP3 Inflammasoms bei der Lupusnephritis
Zusammenfassung der Projektergebnisse
The NLRP3/ASC inflammasome drives host defense and auto-inflammatory disorders by activating caspase-1 to trigger the secretion of mature IL-1β/IL-18. Our analysis indicates that NLRP3 and ASC have a previously unknown role in preventing lymphocyte necrosis in the context of aberrant lupus-like autoimmunity, and enhanced lymphocyte necrosis in B6lpr/lpr mice drives immune activation, lymphocyte proliferation, and tissue injury. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous pro-inflammatory mediators, and the expansion of most T and B cell subsets. In contrast, plasma cells and lupus autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC most likely related to their role in SMAD2/3 phosphorylation during TGF-beta receptor signaling, e.g. Nlrp3- and Asc-deficiency significantly suppressed the expression of numerous TGF-beta target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-beta1-deficient mice. These data identify a novel non-canonical immune-regulatory function of NLRP3 and ASC in lupus nephritis-related autoimmunity, due to their interference with TGF-beta receptor signaling. Our finding somehow parallels the unexpected phenotype of TLR9-deficient lupus mice, which was also unexpected given the known role of this pattern recognition receptor in host defense. Furthermore, our study links too important subjects in immunology, inflammasomerelated innate and TGF-mediated regulation of adaptive immunity.
Projektbezogene Publikationen (Auswahl)
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(2019) STAT1 regulates macrophage number and phenotype and prevents renal fibrosis after ischemia-reperfusion injury. American journal of physiology. Renal physiology 316 (2) F277-F291
Kemmner, Stephan; Bachmann, Quirin; Steiger, Stefanie; Lorenz, Georg; Honarpisheh, Mohsen; Foresto-Neto, Orestes; Wang, Shijun; Carbajo-Lozoya, Javier; Alt, Verena; Schulte, Christian; Chmielewski, Stefan; Bluyssen, Hans A. R.; Heemann, Uwe; Baumann, Marc
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Expression profiling by real-time quantitative polymerase chain reaction (RT qPCR). Methods Mol Biol. 2014; 1169:133-42
Lech M, Anders HJ
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NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling. Ann Rheum Dis. 2015 Dec; 74(12):2224-35
Lech M, Lorenz G, Kulkarni OP, Grosser MO, Stigrot N, Darisipudi MN, Günthner R, Wintergerst MW, Anz D, Susanti HE, Anders HJ
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How Kidney Cell Death Induces Renal Necroinflammation. Semin Nephrol. 2016 May; 36(3):162-73
Mulay SR, Kumar SV, Lech M, Desai J, Anders HJ
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Immunomodulatory Molecule IRAK-M Balances Macrophage Polarization and Determines Macrophage Responses during Renal Fibrosis. J Immunol. 2017 Aug 15;199(4):1440-1452
Steiger S, Kumar SV, Honarpisheh M, Lorenz G, Günthner R, Romoli S, Gröbmayr R, Susanti HE, Potempa J, Koziel J, Lech M
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Toll-like receptor activation in the pathogenesis of lupus nephritis. Clin Immunol. 2017 Dec;185:86-94
Lorenz G, Lech M, Anders HJ
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Aristolochic acid I determine the phenotype and activation of macrophages in acute and chronic kidney disease. Sci Rep. 2018 Aug 15;8(1):12169
Honarpisheh M, Foresto-Neto O, Steiger S, Kraft F, Koehler P, von Rauchhaupt E, Potempa J, Adamowicz K, Koziel J, Lech M
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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
