| Autor: |
Richoz N; Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom.; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA., Tuong ZK; Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom.; Cellular Genetics programme, Wellcome Sanger Institute, Hinxton, United Kingdom., Loudon KW; Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom., Patiño-Martínez E; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA., Ferdinand JR; Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom., Portet A; Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom., Bashant KR; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA., Thevenon E; Novartis Institutes for BioMedical Research, Basel, Switzerland., Rucci F; Novartis Institutes for BioMedical Research, Basel, Switzerland., Hoyler T; Novartis Institutes for BioMedical Research, Basel, Switzerland., Junt T; Novartis Institutes for BioMedical Research, Basel, Switzerland., Kaplan MJ; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA., Siegel RM; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Novartis Institutes for BioMedical Research, Basel, Switzerland., Clatworthy MR; Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom.; Cellular Genetics programme, Wellcome Sanger Institute, Hinxton, United Kingdom. |
| Abstrakt: |
Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis-associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications - TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen. |
