Amplification of autoimmune organ damage by NKp46-activated ILC1s

Stylianos-Iason Biniaris-Georgallis, Tom Aschman, Katerina Stergioula, Frauke Schreiber, Vajiheh Jafari, Anna Taranko, Tejal Karmalkar, Ana Kasapi, Tihana Lenac Rovis, Vedrana Jelencic, David A. Bejarano, Lea Fabry, Michail Papacharalampous, Irene Mattiola, Martina Molgora, Jinchao Hou, Karolin W. Hublitz, Frederik Heinrich, Gabriela Maria Guerra, Pawel Durek, Giannino Patone, Eric L. Lindberg, Henrike Maatz, Oliver Hölsken, Gerhard Krönke, Arthur Mortha, Reinhard E. Voll, Alexander J. Clarke, Anja E. Hauser, Marco Colonna, Kevin Thurley, Andreas Schlitzer, Christoph Schneider, Efstathios G. Stamatiades, Mir-Farzin Mashreghi, Stipan Jonjic, Norbert Hübner, Andreas Diefenbach (), Masatoshi Kanda () and Antigoni Triantafyllopoulou ()
Additional contact information
Stylianos-Iason Biniaris-Georgallis: Charité-Universitätsmedizin Berlin Campus Mitte
Tom Aschman: Charité-Universitätsmedizin Berlin Campus Mitte
Katerina Stergioula: Charité-Universitätsmedizin Berlin Campus Mitte
Frauke Schreiber: Charité-Universitätsmedizin Berlin Campus Mitte
Vajiheh Jafari: Charité-Universitätsmedizin Berlin Campus Mitte
Anna Taranko: Charité-Universitätsmedizin Berlin Campus Mitte
Tejal Karmalkar: Charité-Universitätsmedizin Berlin Campus Mitte
Ana Kasapi: Charité-Universitätsmedizin Berlin Campus Mitte
Tihana Lenac Rovis: University of Rijeka
Vedrana Jelencic: University of Rijeka
David A. Bejarano: University of Bonn
Lea Fabry: Charité-Universitätsmedizin Berlin Campus Mitte
Michail Papacharalampous: University of Freiburg
Irene Mattiola: A Leibniz Institute
Martina Molgora: Washington University School of Medicine
Jinchao Hou: Washington University School of Medicine
Karolin W. Hublitz: Charité-Universitätsmedizin Berlin Campus Benjamin Franklin
Frederik Heinrich: A Leibniz Institute
Gabriela Maria Guerra: A Leibniz Institute
Pawel Durek: A Leibniz Institute
Giannino Patone: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Eric L. Lindberg: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Henrike Maatz: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Oliver Hölsken: A Leibniz Institute
Gerhard Krönke: Charité-Universitätsmedizin Berlin Campus Mitte
Arthur Mortha: University of Toronto
Reinhard E. Voll: University of Freiburg
Alexander J. Clarke: University of Oxford
Anja E. Hauser: Charité-Universitätsmedizin Berlin Campus Mitte
Marco Colonna: Washington University School of Medicine
Kevin Thurley: A Leibniz Institute
Andreas Schlitzer: University of Bonn
Christoph Schneider: University of Zurich
Efstathios G. Stamatiades: Charité-Universitätsmedizin Berlin Campus Benjamin Franklin
Mir-Farzin Mashreghi: A Leibniz Institute
Stipan Jonjic: University of Rijeka
Norbert Hübner: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Andreas Diefenbach: A Leibniz Institute
Masatoshi Kanda: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Antigoni Triantafyllopoulou: Charité-Universitätsmedizin Berlin Campus Mitte

Nature, 2024, vol. 634, issue 8035, 952-960

Abstract: Abstract In systemic lupus erythematosus, loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here we set out to dissect layers and hierarchies of autoimmune kidney inflammation to identify tissue-specific cellular hubs that amplify autoinflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blockade and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILCs) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signalling in a distinct subset of group 1 ILCs (ILC1s) instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILCs promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody clone mNCR1.15; ref. 2) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data provide support for the idea that NKp46+ ILC1s promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1s therefore constitutes a previously unrecognized, crucial tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.

Date: 2024
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DOI: 10.1038/s41586-024-07907-x

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