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Transcriptomic analysis and High dimensional phenotypic mapping of mononuclear phagocytes in mesenteric lymph nodes reveal differences between ulcerative colitis and Crohn's disease.

BACKGROUND & AIM
Crohn's disease (CD) and ulcerative colitis (UC) are distinct forms of inflammatory bowel diseases. Heterogeneity of HLA-DR+SIRPα+ mononuclear phagocytes (MNPs), including macrophages (MΦ), monocyte-derived 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, 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 monocytes/MΦ morphology and phagocytic function was a distinct feature of UC MLNs. In CD, the proportion of CD14-CD64-CD163- (DC-like) cells augmented relative to Mono/MΦ-like cells; DC-like cells drove naive T cell proliferation, Th1 polarization 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.