RESUMO
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.
Assuntos
Imunidade Inata , Nefrite Lúpica , Macrófagos , Receptor 1 Desencadeador da Citotoxicidade Natural , Animais , Camundongos , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Humanos , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Nefrite Lúpica/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Feminino , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/patologia , Masculino , Linfócitos/imunologia , Linfócitos/metabolismo , Rim/patologia , Rim/imunologia , Rim/metabolismo , Antígenos Ly/metabolismo , Autoanticorpos/imunologia , Autoimunidade , Análise de Célula Única , Transdução de Sinais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Intravital microscopy is an invaluable tool to study in real time the dynamic behavior of leukocytes in vivo. We describe herein a simple protocol for time-lapse imaging of tissue-resident macrophages in intact kidney, liver, and spleen in live mice. This method can be used in any commercially available inverted confocal microscope, doesn't require expensive lasers or optics, exhibits minimal organ perturbation, photo bleaching, or phototoxicity, and, hence, it enables the study of tissue-resident macrophages in situ and in vivo under steady state and inflammation.