Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases

Abstract

Background The incidence of pediatric inflammatory bowel disease (PIBD) has been steadily increasing globally. Delayed diagnosis of PIBD increases the risk of complications and contributes to growth retardation. To improve long-term outcomes, there is a pressing need to identify novel markers for early diagnosis of PIBD. Methods The candidate biomarkers for PIBD were identified from the GSE117993 dataset by two machine learning algorithms, namely LASSO and mSVM-RFE, and externally validated in the GSE126124 dataset and our PIBD cohort. The role of ficolin-1 (FCN1) in PIBD and its association with macrophage infiltration was investigated using the CIBERSORT method and enrichment analysis of the single-cell dataset GSE121380, and further validated using immunoblotting, qRT-PCR, and immunostaining in colon biopsies from PIBD patients, a juvenile murine DSS-induced colitis model, and THP-1-derived macrophages. Results FCN1 showed great diagnostic performance for PIBD in an independent clinical cohort with the AUC of 0.986. FCN1 expression was upregulated in both colorectal biopsies and blood samples from PIBD patients. Functionally, FCN1 was associated with immune-related processes in the colonic mucosa of PIBD patients, and correlated with increased proinflammatory M1 macrophage infiltration. Furthermore, single-cell transcriptome analysis and immunostaining revealed that FCN1 was almost exclusively expressed in macrophages infiltrating the colonic mucosa of PIBD patients, and these FCN1+ macrophages were related to hyper-inflammation. Notably, proinflammatory M1 macrophages derived from THP-1 expressed high levels of FCN1 and IL-1β, and FCN1 overexpression in THP-1-derived macrophages strongly promoted LPS-induced activation of the proinflammatory cytokine IL-1β via the NLRP3-caspase-1 axis. Conclusions FCN1 is a novel and promising diagnostic biomarker for PIBD. FCN1+ macrophages enriched in the colonic mucosa of PIBD exhibit proinflammatory phenotypes, and FCN1 promotes IL-1β maturation in macrophages via the NLRP3-caspase-1 axis.

Blockade of V‐domain immunoglobulin suppressor of T‐cell activation reprograms tumour‐associated macrophages and improves efficacy of PD‐1 inhibitor in gastric cancer

“…Furthermore, we found α‐VISTA‐treated TAMs showed decreased expression of TAP2 , LAPTM4B , CXCL12 , LTC4S and NRROS , yet increased expression of FCN1 , GFAP , CCL19 and CLEC6A , indicating a proinflammatory phenotype after blockade of VISTA (Figure 5B,C ). 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 Blockade of VISTA activated the genes associated with immune responses (Figure 5D ), especially the genes modulating proinflammatory phenotype of macrophages and CD8 + T‐cell activation (Figure 5E ). By means of FC/ICFC, we also validated that blockade of VISTA significantly up‐regulated the expression of TNF‐α and IL‐12, yet down‐regulated the expression of Arg‐1 and LAP/TGF‐β within TAMs (Figures 5F and S10 ).…”

Investigating cellular similarities and differences between upper tract urothelial carcinoma and bladder urothelial carcinoma using single-cell sequencing

“…Among these, the top 30 marker genes of UTUC cluster 1 were primarily associated with GO terms related to ribosomes, cell-substrate junctions, and focal adhesions, suggesting their high proliferative nature and active engagement in protein synthesis, along with strong interactions with the surrounding ECM. UTUC cluster 3, on the other hand, appeared to have immunoregulatory functions, as indicated by enriched terms such as ficolin-1-rich granule and lumen ( 66 ). Interestingly, marker genes of UTUC cluster 4 were associated with the regulation of peptidase activity, secretory granule lumen, and cytoplasmic vesicle lumen, suggesting that these tumor cells were characterized by active secretion and vesicular transport.…”

Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in DCM by Bioinformatics Analysis

“…It has been suggested that manipulation of MVP activity may be an attractive therapeutic target in osteoclast-related bone diseases such as osteoporosis [29]. Macrophage MVP, Fer-1 may alleviate in ammation by inhibiting the NF-κB signaling pathway [30,31], FCN1 promotes IL-1β maturation in macrophages via the NLRP1-caspase-3 axis [32], and SULT1C2 may be a good immunotherapeutic target [33].…”