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Depression Exacerbates Dextran Sulfate Sodium-Induced Colitis via IRF5-Mediated Macrophage Polarization

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Abstract

Background and Aims

Patients with inflammatory bowel disease (IBD) and concurrent depression are predisposed to severer disease activity and a worse prognosis. Macrophage polarization toward the M1 phenotype may contribute to the exacerbation of IBD with comorbid depression. Moreover, interferon regulatory factor 5 (IRF5) is involved in the pathogenesis of IBD. The aim of this study was to explore the role of IRF5 in macrophage polarization in the impact of depression upon colitis.

Methods

Depressive-like behavior was induced by repeated forced swim stress. Colon length, disease activity index (DAI), colon morphology, histology, ultrastructure of epithelial barrier, lamina propria macrophage polarization, and expression of IRF5 were compared between DSS colitis rats with and without depressive-like behavior. IRF5 shRNA was constructed to affect the rat peritoneal macrophages polarization in vitro. After IRF5 shRNA lentivirus was introduced into colon by enema, the colitis severity, lamina propria macrophage polarization, and TNF-α, IL-1β, and IL-10 of colon tissues were measured.

Results

The study found severer colonic inflammation in depressed versus non-depressed DSS-colitis rats. Depressed DSS-colitis rats exhibited smaller subepithelial macrophages size and reduced intracellular granule diversity compared with nondepressed DSS-colitis rats. Increased polarization toward the M1 phenotype, elevated expression of IRF5, and co-expression of IRF5 with CD86 were found in depressed versus nondepressed DSS-colitis rats. Lentivirus-mediated shRNA interference with IRF5 expression switched rat peritoneal macrophage polarization from the M1 to the M2 phenotype, downregulated TNF-α, IL-1β expression to a greater extent in depressed versus nondepressed colitis rats.

Conclusions

IRF5-mediated macrophage polarization may likely underlie the deterioration of DSS-induced colitis caused by depression.

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Acknowledgments

The authors thank the Core Facility of West China Hospital for experimental technical assistance. The authors also thank Li Li, Fei Chen and Chunjuan Bao from the Institute of Clinical Pathology, West China Hospital of Sichuan University, for processing histological staining.

Funding

This work was supported by Grants from National Natural Science Fund of China (No. 81770550) and 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2018HXFH054).

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Authors and Affiliations

  1. Department of Gastroenterology, West China Hospital of Sichuan University, No. 37 Guoxue Street, Chengdu, Sichuan, China

    Chang Liang, Yu Tang, Xin Gao, Na Lei, Ying Luo, Pingrun Chen, Shihao Duan, Yubin Cao, Yi Yang & Yan Zhang

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  1. Chang Liang
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Contributions

CL performed most of the experiments and played a key role in preparing the manuscript; YT performed a significant part of the experiments. XG, NL, YL, PC collected the data and planned the study. SD, YC, YY interpreted data, and YZ was involved in project inception, design, supervision, and manuscript revision. All authors contributed to the article and approved the submitted version.

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Correspondence to Yan Zhang.

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Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

The animal study was reviewed and approved by the Animal Studies Committee of West China Hospital of Sichuan University.

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Supplementary Information

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10620_2022_7679_MOESM1_ESM.tif

Supplementary Fig. 1. Effect of lentivirus-mediated shRNA-IRF5 interference on IRF5+ macrophages in the colonic mucosa and submucosa of rat. IRF5 shRNA treatment resulted in a dramatic down-regulation of IRF5 in CD68+ macrophages that infiltrated in the colonic mucosa and submucosa. Representative immunofluorescence images of colonic specimens for staining of IRF5 (green), CD68 (red) and DAPI (blue) (A). The lower three panels (magnification 400x, scale bar =20µm) showed the enlargement of the mucosa in the colon at the same section of the rectangular portion of the upper panel (magnification 50x, scale bar =200µm). The bar charts show the number ratios of IRF5+ and CD68+ co-expression cells, and positive cells were averaged in 10 randomly selected nonoverlapping high-power fields (B). A-B: n=4 rats per group. The data are presented as the mean ± SD. For all panels: *p<0.05, **p<0.01, ***p<0.001 by one-way ANOVA. Abbreviations: Control + NS, control rats with normal saline administered intrarectally; Control + NC-shRNA, control rats treated with NC-shRNA lentiviral vector; Control + IRF5-shRNA, control rats with intrarectal administration of IRF5-shRNA lentiviral (TIF 29296 kb)

Supplementary file2 (DOC 37 kb)

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Liang, C., Tang, Y., Gao, X. et al. Depression Exacerbates Dextran Sulfate Sodium-Induced Colitis via IRF5-Mediated Macrophage Polarization. Dig Dis Sci 68, 1269–1279 (2023). https://doi.org/10.1007/s10620-022-07679-2

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  • DOI: https://doi.org/10.1007/s10620-022-07679-2

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