Multi-scale computational dissection of a pro-inflammatory complement-macrophage interaction circuit in rheumatoid arthritis tissue

The complement system is a central mediator of innate immunity and is widely implicated in autoimmune and inflammatory diseases, including rheumatoid arthritis (RA). However, how complement activity is organized across human cellular states and spatial tissue architecture, and how this organization influences pathogenic inflammation and tissue homeostasis, remain poorly defined. In this study, we establish a multiscale, system-level framework that integrates single-cell meta-analysis, complement-dependent macrophage-fibroblast co-culture assays, and a novel spatial neighborhood-based modeling for gene-level associations for transcriptomic data to define a landscape of the complement-cellular activation map, and uncover a pro-inflammatory complement-macrophage axis as a potential pathogenic hub for RA.

Tutorials

• Spatial neighborhood-based modeling for gene-level associations using spatial transcriptomics data
  Identifying spatially organized complement-associated programs and cellular niches that segregate across synovial lining and sublining compartments.

• Single-cell CITE-seq meta-analysis
  Mapping complement components from different activation pathways to the identified synovial cell states through meta-analysis.

• Bulk RNA-seq to identify complement treatment effect
  Uncovering complement treatment effects through functional perturbation experiments using complement-dependent macrophage-fibroblast co-culture assays.

Citations

Guo, N., Mantel, I., Vargas, J., Inamo, J., Jonsson, A. H., Woodruff, T. M., Banda, N. K., Goodman, S. M., Holers, V. M., Donlin, L. T. & Zhang, F. Multi-scale computational dissection of a pro-inflammatory complement–macrophage interaction circuit in rheumatoid arthritis tissue. In submission.

Help, Suggestions, and Contributions

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Contact

Please contact fanzhanglab@gmail.com for further questions or potential collaborative opportunities!