Multi-source analysis identifies an NPC2-associated macrophage transcriptional program in ulcerative colitis
Abstract
BackgroundUlcerative colitis (UC) involves extensive remodeling of intestinal macrophage states, but the molecular programs linking inflammation, lysosomal function, and lipid handling remain incompletely understood. This study aimed to identify macrophage-associated molecules and cellular states linked to UC.MethodsWe integrated UC single-cell RNA sequencing, bone marrow-derived macrophage polarization transcriptomes, UK Biobank OLINK proteomic associations, external bulk transcriptomic datasets, and spatial transcriptomics. Candidate molecules were further examined in dextran sulfate sodium-induced colitis and macrophage activation models. Differential expression, pathway enrichment, receiver operating characteristic, and Spearman correlation analyses were performed as appropriate.ResultsTwelve genes were shared among UC-associated macrophage differentially expressed genes, macrophage polarization-related genes, and UC-associated circulating protein signals. NPC2 was prioritized based on its macrophage enrichment, external transcriptomic performance, and established lysosomal function. Single-cell reclustering identified an NPC2+MMP12+ macrophage subset with heterogeneous abundance across donors. Donor-level analysis showed a numerically higher median proportion of NPC2+MMP12+ macrophages in UC than in controls, but the difference was not statistically significant (17.7% vs. 9.3%; two-sided Wilcoxon rank-sum test, P = 0.471). NPC2-high macrophages exhibited enrichment of lysosomal, phagocytic, complement, lipid-handling, antigen-presentation, and tissue-remodeling programs. Spatial transcriptomic analysis revealed a positive association between NPC2 expression and macrophage-related signatures in inflamed mucosal regions. NPC2 expression was also increased in DSS-induced colitis and inflammatory macrophage models. Cholesteryl sulfate sodium (CSS) reduced nitrite production and shifted macrophage marker expression away from CD86 predominance, although NPC2 dependence was not established.ConclusionsNPC2 is associated with a lysosome-related macrophage transcriptional program observed in UC. These exploratory findings support further investigation of macrophage lysosomal lipid handling and warrant functional and independent clinical validation.
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BibTeX
@article{chen2026multisource,
title = {{Multi-source analysis identifies an NPC2-associated macrophage transcriptional program in ulcerative colitis}},
author = {Yuhua Chen and Wenwen Yang and Kui Wang and Qinghong Guo},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1968740},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1968740},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Multi-source analysis identifies an NPC2-associated macrophage transcriptional program in ulcerative colitis
AU - Yuhua Chen
AU - Wenwen Yang
AU - Kui Wang
AU - Qinghong Guo
PY - 2026
DA - 2026/11/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1968740
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1968740
AB - BackgroundUlcerative colitis (UC) involves extensive remodeling of intestinal macrophage states, but the molecular programs linking inflammation, lysosomal function, and lipid handling remain incompletely understood. This study aimed to identify macrophage-associated molecules and cellular states linked to UC.MethodsWe integrated UC single-cell RNA sequencing, bone marrow-derived macrophage polarization transcriptomes, UK Biobank OLINK proteomic associations, external bulk transcriptomic datasets, and spatial transcriptomics. Candidate molecules were further examined in dextran sulfate sodium-induced colitis and macrophage activation models. Differential expression, pathway enrichment, receiver operating characteristic, and Spearman correlation analyses were performed as appropriate.ResultsTwelve genes were shared among UC-associated macrophage differentially expressed genes, macrophage polarization-related genes, and UC-associated circulating protein signals. NPC2 was prioritized based on its macrophage enrichment, external transcriptomic performance, and established lysosomal function. Single-cell reclustering identified an NPC2+MMP12+ macrophage subset with heterogeneous abundance across donors. Donor-level analysis showed a numerically higher median proportion of NPC2+MMP12+ macrophages in UC than in controls, but the difference was not statistically significant (17.7% vs. 9.3%; two-sided Wilcoxon rank-sum test, P = 0.471). NPC2-high macrophages exhibited enrichment of lysosomal, phagocytic, complement, lipid-handling, antigen-presentation, and tissue-remodeling programs. Spatial transcriptomic analysis revealed a positive association between NPC2 expression and macrophage-related signatures in inflamed mucosal regions. NPC2 expression was also increased in DSS-induced colitis and inflammatory macrophage models. Cholesteryl sulfate sodium (CSS) reduced nitrite production and shifted macrophage marker expression away from CD86 predominance, although NPC2 dependence was not established.ConclusionsNPC2 is associated with a lysosome-related macrophage transcriptional program observed in UC. These exploratory findings support further investigation of macrophage lysosomal lipid handling and warrant functional and independent clinical validation.
SN - 1664-3224
ER -