Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis
Nathan Richoz, Zewen K. Tuong, Kevin W. Loudon, Eduardo Patiño-Martínez, John R. Ferdinand, Jorge Romo-Tena, Anaïs Portet, Kathleen R. Bashant, Emeline Thevenon, Francesca Rucci, Thomas Hoyler, Tobias Junt, Mariana J. Kaplan, Richard M. Siegel, Menna R. Clatworthy
Nathan Richoz, Zewen K. Tuong, Kevin W. Loudon, Eduardo Patiño-Martínez, John R. Ferdinand, Jorge Romo-Tena, Anaïs Portet, Kathleen R. Bashant, Emeline Thevenon, Francesca Rucci, Thomas Hoyler, Tobias Junt, Mariana J. Kaplan, Richard M. Siegel, Menna R. Clatworthy
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Research Article Immunology

Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis

Abstract

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.

Authors

Nathan Richoz, Zewen K. Tuong, Kevin W. Loudon, Eduardo Patiño-Martínez, John R. Ferdinand, Jorge Romo-Tena, Anaïs Portet, Kathleen R. Bashant, Emeline Thevenon, Francesca Rucci, Thomas Hoyler, Tobias Junt, Mariana J. Kaplan, Richard M. Siegel, Menna R. Clatworthy

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Figure 8

Human kidney MNPs show perturbations in FcγR expression, activation, and interactions in lupus nephritis.

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Human kidney MNPs show perturbations in FcγR expression, activation, and...
(A) Integrated UMAP embedding of macrophages from publicly available data sets of human kidneys (normal, ref. 37, and SLE, ref. 38). (B) Heatmap of mean AUCell enrichment of mouse group 1 and group 2 signatures in human macrophage clusters. (C) Heatmap of mean AUCell enrichment of OIC cross-linking signature split by normal or SLE. (D) Violin plot of Tnfsf13b in human macrophage clusters. Expression value is scaled from 0 to 1 across cell clusters. Significance was calculated using Wilcoxon rank sum test with BH posttest applied where ***P < 0.001. Color of the P value indicates which group has a higher value (red = SLE, blue = normal). (E) Microscopy showing BAFF expression (red) in peri-glomerular macrophages (CD206, cyan) in kidneys from SLE patients. Scale bar = 20 μm. (F) CellPhoneDB receptor-ligand interaction analysis between human B cells and human macrophage clusters (NC — nonclassical monocyte-derived macrophages; C – classical monocyte-derived macrophages; TR — tissue resident macrophages) split by normal (N) or SLE (S). Significant interactions (P < 0.05) are highlighted in red. (G) Violin plot of BAFF receptor molecules in human B cells. Expression value is scaled from 0 to 1. Significance was calculated using Wilcoxon rank sum test with BH posttest applied where ***P < 0.001. Color of the P value indicates which group has a higher value (red = SLE, blue = normal).