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Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization

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Abstract

Objective and design

Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD.

Methods

The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes.

Results

Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo.

Conclusion

Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

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Data availability

To obtain the RNA-seq data, check the website with the accession number PRJNA1034166 on https://www.ncbi.nlm.nih.gov/bioproject.

Abbreviations

ARG-1:

Arginase-1

BA:

Bile acid

BMDMs:

Bone marrow-derived macrophages

CD:

Crohn’s disease

CRC:

Colorectal cancer

CYP7A1:

Cytochrome P450 family 7 subfamily A member 1

C3ar1:

C3a receptor1

DAI:

Disease activity index

DSS:

Dextran sulfate sodium

FGF19:

Fibroblast growth factor 19

FGFR4:

Fibroblast growth factor receptor 4

HCC:

Hepatocellular carcinoma

IBD:

Inflammatory bowel disease

IBS-D:

Irritable bowel syndrome combined with diarrhea

IFN-γ:

Interferon gamma

IL-1β:

Interleukin-1 beta

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

NF-ΚB:

Nuclear factor-kappa B

PD-L1:

Programmed death ligand 1

p-IKKβ:

Phosphorylated kinase

PTX3:

Pentraxin3

p-IKBα:

Phosphorylated inhibitor kappa B alpha

TAMs:

Tumor-associated macrophages

TLR:

Toll-like receptor

TME:

Tumor microenvironment

TNF-α:

Tumor necrosis factor alpha

UC:

Ulcerative colitis

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Funding

This work was supported by the Major International (Regional) Joint Research Program of the National Natural Science Foundation of China (No. 81920108027 to Y.L.), National Natural Science Foundation of China (No. 82273212 to H.Z.), Chongqing Young and Middle-aged Medical Talents Project (to H.Z.), Funding for Chongqing Young and Middle-Aged Medical Excellence Team (to Y.L.), Research and breeding project of Chongqing Medical Biotechnology Association (No. cmba2022kyym-zkxmQ0006 to H.Z), and Performance Incentive for Scientific Research Institutions of Chongqing Guide Special Projects (No. cstc2020jxjl130014 to H.Z.).

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Author notes

  1. Luyao Shen and Cong Wang contributed equally to this work.

Authors and Affiliations

  1. The Second Affiliated Hospital & Yuying Children’s Hospital, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325030, Zhejiang, China

    Luyao Shen, Dongqin Zhou & Yongsheng Li

  2. School of Pharmacy, Wenzhou Medical University, Wenzhou, 325030, Zhejiang, China

    Cong Wang

  3. Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China

    Ran Ren, Xudong Liu, Yu Chen, Yu Zhou, Juan Lei, Yang **ao, Nan Zhang, Huakan Zhao & Yongsheng Li

  4. School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400044, China

    Ran Ren, Xudong Liu, Yang **ao, Nan Zhang, Huakan Zhao & Yongsheng Li

Authors
  1. Luyao Shen
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  2. Cong Wang
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  3. Ran Ren
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  6. Yu Chen
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  7. Yu Zhou
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  8. Juan Lei
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  10. Nan Zhang
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  11. Huakan Zhao
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Contributions

Luyao Shen: Investigation, Data Curation, Writing-Original Draft. Cong Wang: Resources, Methodology. Ran Ren: Investigation. Xudong Liu: Visualization. Dongqin Zhou: Methodology. Yu Chen: Methodology. Yu Zhou: Investigation. Juan Lei: Methodology, Data Curation. Yang **ao: Formal analysis, Data Curation. Nan Zhang: Validation. Huakan Zhao: Conceptualization, Writing – Review & Editing, Funding acquisition. Yongsheng Li: Supervision, Project administration, Writing - Review & Editing, Funding acquisition. All authors reviewed the manuscript.

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Correspondence to Huakan Zhao or Yongsheng Li.

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Shen, L., Wang, C., Ren, R. et al. Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization. Inflamm. Res. (2024). https://doi.org/10.1007/s00011-024-01910-8

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