The landscape of immune dysregulation in Crohn’s disease revealed through single-cell transcriptomic profiling in the ileum and colon
Lingjia Kong, Vladislav Pokatayev, Ariel Lefkovith, Grace T. Carter, Elizabeth A. Creasey, Chirag Krishna, Sathish Subramanian, Bharati Kochar, Orr Ashenberg, Helena Lau, Ashwin N. Ananthakrishnan, Daniel B. Graham, Jacques Deguine, Ramnik J. Xavier
Abstract
Crohn’s disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors, necessitating a system-level understanding of its etiology. To characterize cell-type-specific transcriptional heterogeneity in active CD, we profiled 720,633 cells from the terminal ileum and colon of 71 donors with varying inflammation status. Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells. These changes correlated with endoscopic inflammation, but small and large intestines exhibited distinct responses, which were particularly apparent when focusing on IBD risk genes. Finally, we mapped markers of disease-associated myofibroblast activation and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications. Altogether, our results provide a roadmap for understanding cell-type- and organ-specific differences in CD and potential directions for therapeutic development.
Datasets
1. TI immune
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T cells CD4 FOSB17131 cells T cells CD4 IL17A11100 cells Macrophages CCL3 CCL48145 cells T cells CD8 KLRG17416 cells IELs ID3 ENTPD15663 cells T cells Naive CD43884 cells NK cells KLRF1 CD3G-3563 cells Macrophages LYVE13217 cells B cells AICDA LRMP1389 cells Macrophages PLA2G2D1228 cells Monocytes S100A8 S100A91145 cells Macrophages CXCL9 CXCL10659 cells Monocytes CHI3L1 CYP27A1115 cells Neutrophils S100A8 S100A969 cells NCBITaxon:9606201072 cells MONDO:0005011183046 cells UBERON:0002116146383 cells UBERON:000834535361 cells UBERON:000210812577 cells HsapDv:000024052229 cells HsapDv:000024146108 cells HsapDv:000023945225 cells HsapDv:000023831856 cells HsapDv:000023720989 cells CD8-positive, alpha-beta T cell28571 cells CD4-positive, alpha-beta T cell28231 cells plasmacytoid dendritic cell8259 cells regulatory T cell7022 cells intraepithelial lymphocyte5663 cells natural killer cell3563 cells conventional dendritic cell2215 cells innate lymphoid cell1137 cells Crohn disease183046 cells ileal epithelium35361 cells small intestine12577 cells lamina propria of small intestine6665 cells epithelium of small intestine86 cells sixth decade human stage52229 cells seventh decade human stage46108 cells fifth decade human stage45225 cells fourth decade human stage31856 cells third decade human stage20989 cells young adult stage4544 cells eighth decade human stage121 cells 2. TI epithelial
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T cells CD4 FOSB18218 cells T cells Naive CD46984 cells Macrophages CCL3 CCL45047 cells Macrophages LYVE14568 cells T cells CD8 KLRG14040 cells NK-like cells ID3 ENTPD13923 cells T cells CD4 IL17A3221 cells Immune Cycling cells2270 cells NK cells KLRF1 CD3G-2233 cells Monocytes S100A8 S100A91676 cells Macrophages Metallothionein1342 cells B cells AICDA LRMP411 cells Monocytes CHI3L1 CYP27A1165 cells NCBITaxon:9606152509 cells UBERON:000897240609 cells UBERON:000717734537 cells UBERON:000115523669 cells UBERON:000115317854 cells UBERON:000115914438 cells UBERON:000897110578 cells HsapDv:000008751345 cells HsapDv:000023725417 cells HsapDv:000023921798 cells HsapDv:000023821655 cells HsapDv:000024011516 cells CD4-positive, alpha-beta T cell21439 cells CD8-positive, alpha-beta T cell9185 cells regulatory T cell4380 cells plasmacytoid dendritic cell3559 cells natural killer cell2233 cells conventional dendritic cell895 cells innate lymphoid cell664 cells lamina propria of mucosa of colon34537 cells transverse colon6956 cells colonic epithelium3514 cells caecum epithelium354 cells human adult stage51345 cells third decade human stage25417 cells fifth decade human stage21798 cells fourth decade human stage21655 cells sixth decade human stage11516 cells eighth decade human stage9452 cells young adult stage5966 cells seventh decade human stage5360 cells 4. colon epithelial
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Enterocytes CA1 CA2 CA4-32783 cells Enterocytes TMIGD1 MEP1A17997 cells Goblet cells MUC2 TFF1-11681 cells Epithelial Cycling cells8187 cells Stem cells OLFM4 LGR57201 cells Stem cells OLFM46440 cells Stem cells OLFM4 PCNA4858 cells Enterocytes BEST42618 cells Goblet cells MUC2 TFF12522 cells Goblet cells SPINK41447 cells Enteroendocrine cells549 cells NCBITaxon:960697788 cells UBERON:000115527758 cells UBERON:000897220870 cells UBERON:000039717553 cells HsapDv:000008729973 cells HsapDv:000024115405 cells HsapDv:000023814793 cells HsapDv:000023912685 cells HsapDv:000024210849 cells epithelial cell8187 cells enteroendocrine cell549 cells colonic epithelium17553 cells lamina propria of mucosa of colon8076 cells transverse colon4402 cells caecum epithelium1300 cells human adult stage29973 cells seventh decade human stage15405 cells fourth decade human stage14793 cells fifth decade human stage12685 cells eighth decade human stage10849 cells third decade human stage8700 cells sixth decade human stage3443 cells young adult stage1940 cells 5. TI stromal
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Fibroblasts ADAMDEC123427 cells Endothelial cells CD369377 cells Myofibroblasts GREM1 GREM26745 cells Endothelial cells DARC6634 cells Endothelial cells CA4 CD364157 cells Fibroblasts SMOC2 PTGIS2904 cells Pericytes HIGD1B STEAP42655 cells Myofibroblasts HHIP NPNT2461 cells Fibroblasts KCNN3 LY6H2342 cells Pericytes RERGL NTRK22274 cells Fibroblasts SFRP2 SLPI2185 cells Fibroblasts NPY SLITRK61786 cells Endothelial cells LTC4S SEMA3G1555 cells Activated fibroblasts CCL19 ADAMADEC1789 cells NCBITaxon:960675695 cells UBERON:000211663937 cells UBERON:000210810467 cells HsapDv:000023946821 cells HsapDv:000024014020 cells endothelial cell21723 cells myofibroblast cell9206 cells small intestine10467 cells lamina propria of small intestine687 cells ileal epithelium604 cells fifth decade human stage46821 cells sixth decade human stage14020 cells third decade human stage6470 cells seventh decade human stage5412 cells fourth decade human stage2555 cells young adult stage417 cells 6. colon stromal
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Fibroblasts ADAMDEC115256 cells Endothelial cells CD365237 cells Fibroblasts SMOC2 PTGIS4158 cells Myofibroblasts HHIP NPNT2371 cells Fibroblasts NPY SLITRK61919 cells Fibroblasts KCNN3 LY6H1746 cells Endothelial cells DARC1507 cells Myofibroblasts GREM1 GREM2955 cells Fibroblasts SFRP2 SLPI860 cells Activated fibroblasts CCL19 ADAMADEC1827 cells Pericytes HIGD1B STEAP4753 cells Stromal Cycling cells321 cells Inflammatory fibroblasts IL11 CHI3L1320 cells Pericytes RERGL NTRK2295 cells Endothelial cells LTC4S SEMA3G230 cells NCBITaxon:960639433 cells UBERON:000897212425 cells UBERON:000115510187 cells HsapDv:000023710758 cells endothelial cell6974 cells myofibroblast cell3326 cells lamina propria of mucosa of colon7677 cells transverse colon1265 cells colonic epithelium10 cells third decade human stage10758 cells human adult stage8619 cells eighth decade human stage6594 cells fourth decade human stage4353 cells young adult stage3866 cells fifth decade human stage3126 cells sixth decade human stage1129 cells seventh decade human stage988 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/5c868b6f-62c5-4532-9d7f-a346ad4b50a7
Alias names
SCP1884, PMID36720220, PMC9957882
Cite this study
Kong, L., Pokatayev, V., Lefkovith, A., Carter, G.T., Creasey, E.A., Krishna, C., Subramanian, S., Kochar, B., Ashenberg, O., Lau, H. and Ananthakrishnan, A.N., 2023. The landscape of immune dysregulation in Crohn’s disease revealed through single-cell transcriptomic profiling in the ileum and colon. Immunity, 56(2), pp.444-458. https://doi.org/10.1016/j.immuni.2023.01.002
