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Lupus-Associated Immune Complexes Induce Shared Proinflammatory Transcriptional Programs in Human Monocytes

ABSTRACT: Lupus-associated immune complexes (ICs) activate monocytes and contribute to disease pathogenesis. Here, we performed microarray analysis of monocytes stimulated with dsDNA ICs, Ro60/anti-Ro60 (Ro) ICs, or snRNP ICs to characterize IC-induced transcriptional responses. All three IC types induced overlapping sets of differentially expressed genes compared with unstimulated monocytes. Pathway enrichment analysis of upregulated genes revealed common activation of immune-related pathways, including NOD-like receptor, NF-κB, TNF, and Toll-like receptor signaling pathways. These results indicate that distinct lupus-associated ICs trigger shared inflammatory programs in monocytes, supporting a common mechanism of IC-driven innate immune activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315667 | GEO | 2026/03/04

REPOSITORIES: GEO

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

Project description: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.

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Dmrt2 and Hmx2 direct intercalated cell diversity in the mammalian kidney through antagonistic and supporting regulatory processes

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