Amplification of autoimmune organ damage by NKp46-activated ILC1s

• 成果类型: Article
• 署名作者: Biniaris-Georgallis, Stylianos-Iason; Aschman, Tom; Stergioula, Katerina; Schreiber, Frauke; Jafari, Vajiheh; Taranko, Anna; Karmalkar, Tejal; Kasapi, Ana; Lenac Rovis, Tihana; Jelencic, Vedrana; Bejarano, David A.; Fabry, Lea; Papacharalampous, Michail; Mattiola, Irene; Molgora, Martina; Hou, Jinchao; Hublitz, Karolin W.; Heinrich, Frederik; Guerra, Gabriela Maria; Durek, Pawel; Patone, Giannino; Lindberg, Eric L.; Maatz, Henrike; Hoelsken, Oliver; Kroenke, Gerhard; Mortha, Arthur; Voll, Reinhard E.; Clarke, Alexander J.; Hauser, Anja E.; Colonna, Marco; Thurley, Kevin; Schlitzer, Andreas; Schneider, Christoph; Stamatiades, Efstathios G.; Mashreghi, Mir-Farzin; Jonjic, Stipan; Huebner, Norbert; Diefenbach, Andreas; Kanda, Masatoshi; Triantafyllopoulou, Antigoni
• 署名单位: Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Leibniz Association; Deutsches Rheuma-Forschungszentrum (DRFZ); Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; University of Freiburg; University of Rijeka; University of Bonn; Washington University (WUSTL); Helmholtz Association; Max Delbruck Center for Molecular Medicine; German Centre for Cardiovascular Research; University of Toronto; University of Oxford; Kennedy Institute for Rheumatology; University of Bonn; University of Zurich; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Sapporo Medical University; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; H Lee Moffitt Cancer Center & Research Institute; Zhejiang University; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4370
• DOI: 10.1038/s41586-024-07907-x
• 发表日期: 2024-10-24
• 关键词: systemic autoimmunity; t-cells; expression

摘要

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. NKp46+ innate lymphoid cells are identified as pivotal signal amplifiers of autoinflammatory responses in lupus nephritis.