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Abstract Number: 2534

Deciphering Complement-dependent Macrophage Phenotypes in Human Rheumatoid Arthritis Using Combined Computational-experimental Single-cell Omics

Juan Vargas1, Ian Mantel2, Jun Inamo3, Nirmal Banda1, Anna Helena Jonsson3, Kevin Wei4, Deepak Rao5, Susan Goodman6, Kevin Deane7, Jennifer Seifert8, Jennifer Anolik9, Michael Brenner10, Soumya Raychaudhuri11, Trent Woodruff12, the Accelerating Medicines Partnership (AMP) RA/SLE Network13, Michael Holers14, Laura Donlin15 and Fan Zhang16, 1The University of Colorado, Aurora, CO, 2WEILL CORNELL MEDICINE, New York, NY, 3University of Colorado School of Medicine, Aurora, CO, 4Brigham and Women's Hospital at Harvard Medical School, Boston, MA, 5Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 6Hospital for Special Surgery, New York 10025, NY, 7University of Colorado Denver Anschutz Medical Campus, Aurora, CO, 8University of Colorado and Oklahoma Medical Research Foundation, Aurora, CO, 9University of Rochester Medical Center, Rochester, NY, 10Brigham Women's Hospital, Boston, MA, 11Brigham and Women's Hospital, Boston, MA, 12University of Queensland, Brisbane, Australia, 13AMP RA/SLE consortium, Aurora, CO, 14Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, 15Hospital for Special Surgery, New York, NY, 16University of Colorado, Aurora, CO

Meeting: ACR Convergence 2024

Keywords: Bioinformatics, complement, Genomics and Proteomics, macrophages, rheumatoid arthritis

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Session Information

Date: Monday, November 18, 2024

Title: Abstracts: Genetics, Genomics & Proteomics

Session Type: Abstract Session

Session Time: 1:00PM-2:30PM

Background/Purpose: The complement system is a major component of innate immunity and plays a vital role in experimental models of autoimmune disease pathogenesis. In patients with rheumatoid arthritis (RA), complement activation proteins generated in the synovium can interact with macrophages, promoting inflammation and disrupting tissue homeostasis for RA. However, it remains to be determined how specific complement components directly modulate cell-type functions. Understanding this may generate alternative therapeutic targets for RA.

Methods: We have generated a comprehensive RA synovial single-cell atlas and classified the spectrum of RA biopsies into six tissue phenotypes (Zhang, et al, Nature, 2023)1. In this current study, we linked single-cell transcriptomic expression of complement activation pathway components and receptors for effector proteins with cell-type heterogeneity and tested significant associations with different tissue types. Next, we characterized myeloid cell differentiation and aligned specific complement gene expression to myeloid functional states. Further, we established an in vitro co-culture system to evaluate the impacts of complement inhibitors on the transcriptional phenotype of macrophages.

Results: We generated a complement cellular graph characterizing interactions between complement components and cell-type patterns in RA synovium. The complement components present unexpected distinct transcriptomic expression across cell types (Fig. 1). Within myeloid cells, we identified a myeloid cell differentiation axis revealing that complement components C1QA-B, C3AR1, and C2 expressions correlated with anti-inflammatory/phagocytic functions; while complement components FCN1 and CFP expression correlated with pro-inflammatory function (Fig. 2). Further, we identified a particular subtype, MERTK+HBEGF+ tissue macrophage, which is enriched in lymphocyte-low tissues and marked by the pro-inflammatory complement 5 receptor C5AR1, and inflammatory TNF signaling pathway-associated signatures like TNF, CXCL2, and CXCL3 (Fig. 3A). Intriguingly, we found that the addition of an inhibitor of C5aR1 suppressed inflammatory and interferon responses, while upregulating tissue protective phagocytic programs (Fig. 3B-C). Moreover, we revealed that the abundance of complement-dependent receptor-ligand (C5AR-C5 and C3AR1-C3) are correlated across RA patients (Fig. 3D), suggesting potential complement pathway crosstalk that impacts synovial macrophages and fibroblasts.

Conclusion: Through systematically aligning complement pathways with synovial heterogeneity, we found that modulating complement pathways in the MERTK+ macrophages could improve homeostatic function. This combined computational-experimental approach in human synovium and ex vivo systems brings insights into new complement pathway-modulated macrophage targets that upon rewiring may restore tissue homeostasis for RA. This is promising to provide a roadmap for other complex pathways in autoimmune disease tissues.

Reference

1.    Zhang, F. et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature 623, 616–624 (2023).

Supporting image 1

Fig. 1. Single-cell expression distributions of complement components across cell types and cell states in rheumatoid arthritis synovial tissues.

Supporting image 2

Fig. 2. Myeloid-specific single-cell trajectory analysis revealed a myeloid cell differentiation trajectory from phagocytic to pro-inflammatory lineage. A. Complement components C1QA-B, C3AR1, and C2 expressions correlated with anti-inflammatory/phagocytic functions, B. Complement components FCN1 and CFP expressions correlated with pro-inflammatory function. Spearman correlation R is shown and p < 2.2 e_16.

Supporting image 3

Fig. 3. The addition of an inhibitor of C5aR1 suppressed inflammatory and interferon responses, while upregulated tissue protective phagocytic programs. A. Unique signatures for METK+HBEGF+ macrophage phenotype by single-cell RNA-seq, B. Effect of C5aR1 antagonist on transcriptional phenotype of tissue macrophages, C. Down-regulated interferon and inflammatory pathways after applying C5aR1, D. Across cell type analyses revealed complement-development receptor-ligand correlations. Spearman correlation and p-value are shown.


Disclosures: J. Vargas: None; I. Mantel: None; J. Inamo: None; N. Banda: None; A. Jonsson: Pfizer, 6; K. Wei: 10X Genomics, 5, Gilead sciences, 2, Merck/MSD, 5, Mestag, 2, santa ana bio, 2; D. Rao: Amgen, 6, AnaptysBio, 2, AstraZeneca, 1, Bristol-Myers Squibb, 2, 5, GlaxoSmithKline, 2, HiFiBio, 2, Janssen, 5, Merck, 5, Scipher Medicine, 2; S. Goodman: Novartis Corporation Pharmaceuticals, 5, UCB, 1; K. Deane: Boehringer-Ingelheim, 5, Bristol-Myers Squibb(BMS), 6, Gilead, 5, Inova, 6, 12, Material Support, ThermoFisher, 5, 6; J. Seifert: None; J. Anolik: None; M. Brenner: GlaxoSmithKlein(GSK), 2, Mestag Therapeutics, 2, 11, Moderna, 2; S. Raychaudhuri: Janssen, 1, Mestag, 8, Nimbus, 2, Pfizer, 1, Sonoma, 8, Third Rock Ventures, 2; T. Woodruff: None; t. RA/SLE Network: None; M. Holers: None; L. Donlin: Bristol-Myers Squibb(BMS), 2, Karius, Inc., 5, Stryker, 2; F. Zhang: None.

To cite this abstract in AMA style:

Vargas J, Mantel I, Inamo J, Banda N, Jonsson A, Wei K, Rao D, Goodman S, Deane K, Seifert J, Anolik J, Brenner M, Raychaudhuri S, Woodruff T, RA/SLE Network t, Holers M, Donlin L, Zhang F. Deciphering Complement-dependent Macrophage Phenotypes in Human Rheumatoid Arthritis Using Combined Computational-experimental Single-cell Omics [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/deciphering-complement-dependent-macrophage-phenotypes-in-human-rheumatoid-arthritis-using-combined-computational-experimental-single-cell-omics/. Accessed .
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