A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis

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Abstract
Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis.
Funding Information
  • Lupus Research Alliance (1244415)
  • Rheumatology Research Foundation (15829669, 998677)
  • National Institute of Allergy and Infectious Diseases (P01AI148102)
  • Department of Defense (W81XWH-21-1-0966)
  • National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK131482-01A1, U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, UH3DK114937)
  • Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases Network
  • National Institutes of Health (UC2-AR081025, UC2-DE032254, UC2-AR081029, UC2-AR081039, UC2-AR081023, UC2-AR081031, UC2-AR081032, UC2-AR081033, UC2-AR081034)

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