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Transcriptomic Analysis and High-dimensional Phenotypic Mapping of Mononuclear Phagocytes in Mesenteric Lymph Nodes
Laurence Chapuy1, Marwa Bsat1, Manuel Rubio1
1Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal [CRCHUM], Montréal, QC, Canada.
Insights
Mononuclear phagocytes (MNPs) in mesenteric lymph nodes differ between Crohn's disease (CD) and ulcerative colitis (UC). UC exhibits increased CD163+ monocyte/macrophage-like cells, suggesting their role in colitis.
Area of Science:
- Immunology
- Gastroenterology
Background:
- Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), involves complex immune dysregulation.
- Distinct subsets of mononuclear phagocytes (MNPs), including macrophages (MΦ), monocytes (Mono), and dendritic cells (DCs), reside in the gut and mesenteric lymph nodes (MLNs).
- Previous studies highlighted MNP heterogeneity in gut tissue, but their specific roles in IBD-associated MLN inflammation remain under-investigated.
Purpose of the Study:
- To compare the phenotype, function, and molecular profiles of HLA-DR+SIRPα+ MNPs within the MLNs of patients with CD and UC.
- To elucidate the distinct contributions of MNP subsets to the immunopathology of CD and UC.
Main Methods:
- Analysis of cell distribution, morphology, immune function, and transcriptomic (bulk RNAseq) and proteomic (CyTOF) profiles of MLN MNPs.
- Comparison of HLA-DR+SIRPα+ MNPs from UC (n=14), CD (n=35), and non-IBD (n=12) control individuals.
Main Results:
- Ulcerative colitis (UC) MLNs showed elevated frequencies of CD14+CD64+CD163+ monocyte/MΦ-like MNPs with enhanced phagocytic capacity.
- Crohn's disease (CD) MLNs exhibited a higher proportion of CD14-CD64-CD163- DC-like cells, which promoted T cell proliferation and Th1/Th17 polarization.
- Transcriptomic and CyTOF analyses identified specific molecular markers distinguishing these MNP subsets and revealed an expansion of CD163+ monocyte/MΦ-like cells in UC.
Conclusions:
- Mesenteric lymph node MNP landscapes reveal distinct profiles in UC and CD.
- Expansion of CD163+ monocyte/MΦ-like cells is a specific feature of UC, suggesting their potential role in driving colitis.
- These findings highlight MNP heterogeneity as a key factor differentiating UC and CD pathogenesis.
Background And Aims:
Crohn's disease [CD] and ulcerative colitis [UC] are distinct forms of inflammatory bowel disease. Heterogeneity of HLA-DR+SIRPα + mononuclear phagocytes [MNPs], including macrophages [MΦ], monocyte-derived [Mono] cells, and dendritic cells [DCs], was reported in gut tissue but not yet investigated in mesenteric lymph nodes [MLNs] of IBD patients. We here compared the phenotype, function, and molecular profile of HLA-DR+SIRPα + MNPs in CD and UC MLNs.
Methods:
Cell distribution, morphology, immune function, and transcriptomic [bulk RNAseq] and high-dimensional protein expression profiles [CyTOF] of HLA-DR+SIRPα + MNPs were examined in MLNs of UC [n = 14], CD [n = 35], and non-IBD [n = 12] patients.
Results:
Elevated frequencies of CD14+CD64+CD163+ [Mono/MΦ-like] MNPs displaying monocyte/MΦ morphology and phagocytic function were a distinct feature of UC MLNs. In CD, the proportion of CD14-CD64-CD163- [DC-like] cells was augmented relative to Mono/MΦ-like cells; DC-like cells drove naïve T cell proliferation, Th1 polarisation, and Th17 TCM plasticity. Gene expression profile corroborated the nature of DC-like cells, best represented by BTLA, SERPINF, IGJ and, of Mono/MΦ-like cells, defined by CD163, MARCO, MAFB, CD300E, S100A9 expression. CyTOF analysis showed that CD123+ plasmacytoid cells predominated over conventional DCs in DC-like cells. Four CD163+ clusters were revealed in Mono/MΦ-like cells, two of which were enriched in MARCO-CD68dimHLA-DRdim monocyte-like cells and MARCOhiCD68hiHLA-DRhi Mɸ, whose proportion increased in UC relative to CD.
Conclusions:
Defining the landscape of MNPs in MLNs provided evidence for expansion of CD163+ Mono/MΦ-like cells in UC only, highlighting a distinction between UC and CD, and thus the potential contribution of monocyte-like cells in driving colitis.
