Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Kessler, N.; Viehmann, S. F.; Krollmann, C.; Mai, K.; Kirschner, K. M.; Luksch, H.; Kotagiri, P.; Boehner, A. M. C.; Huugen, D.; de Oliveira Mann, C. C.; Otten, S.; Weiss, S. A. I.; Zillinger, T.; Dobrikova, K.; Jenne, D. E.; Ablasser, A.; Bartok, E.; Hartmann, G.; Hopfner, K.-P.; Lyons, P. A.; Boor, P.; Roesen-Wolff, A.; Teichmann, L.; Heeringa, P.; Kurts, C.; Garbi, N.

doi:10.1101/2022.05.30.493983

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bioRxiv · 10.1101/2022.05.30.493983

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

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Abstract

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-{beta}, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-{beta}-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/493983v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@521964org.highwire.dtl.DTLVardef@13506org.highwire.dtl.DTLVardef@1403dbeorg.highwire.dtl.DTLVardef@958cc4_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryKessler et al. identify aberrant DNA recognition by cGAS/STING axis and IFN-I production by inflammatory macrophages as a major driver of severe ANCA-associated vasculitis (AAV). Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.

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Kessler, N., Viehmann, S. F., Krollmann, C., Mai, K., Kirschner, K. M., Luksch, H., Kotagiri, P., Boehner, A. M. C., Huugen, D., de Oliveira Mann, C. C., Otten, S., Weiss, S. A. I., Zillinger, T., Dobrikova, K., Jenne, D. E., Ablasser, A., Bartok, E., Hartmann, G., Hopfner, K.-P., Lyons, P. A., Boor, P., Roesen-Wolff, A., Teichmann, L., Heeringa, P., Kurts, C., Garbi, N.. 2022-05-30. Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing. https://doi.org/10.1101/2022.05.30.493983

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