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Chromogranin-A Regulates Macrophage Function and the Apoptotic Pathway in Murine DSS colitis

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Abstract

Chromogranin-A (CHGA) is elevated in inflammatory bowel disease (IBD), but little is known about its role in colonic inflammation. IBD is associated with impaired functions of macrophages and increased apoptosis of intestinal epithelial cells. We investigated CHGA expression in human subjects with active ulcerative colitis (UC) and the underlying mechanisms in Chga −/− mice. In UC, CHGA, classically activated macrophage (M1) markers, caspase-3, p53, and its associated genes were increased, while alternatively activated macrophage (M2) markers were decreased without changes in the extrinsic apoptotic pathway. CHGA correlated positively with M1 and the apoptotic pathway and negatively with M2. In the murine dextran sulfate sodium (DSS)-induced colitis, Chga deletion reduced the disease severity and onset, pro-inflammatory mediators, M1, and p53/caspase-3 activation, while it upregulated anti-inflammatory cytokines and M2 markers with no changes in the extrinsic apoptotic markers. Compared to Chga +/+, M1 and p53/caspase-3 activation in Chga −/− macrophages were decreased in vitro, while M2 markers were increased. CHGA plays a critical role during colitis through the modulation of macrophage functions via the caspase-3/p53 pathway. Strategies targeting CHGA to regulate macrophage activation and apoptosis might be developed to treat UC patients.

Key messages

• Chromogranin-A (CHGA) is pro-hormone and is secreted in the gut. CHGA is elevated in colitis and is associated with the disease severity. The lack of GHGA has beneficial immunomodulatory properties during the development of intestinal inflammation. The lack of CHGA regulates the plasticity of macrophages and p53/caspase activation in colitis. Functional analysis of CHGA may lead to a novel therapy for IBD.

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Funding

This study was supported by grants from the Canadian Foundation for Innovation, Crohn’s and Colitis Canada, Research Manitoba, Children’s Hospital Research Institute of Manitoba, and the Canadian Institutes of Health Research to Jean-Eric Ghia. Nour Eissa is funded and supported by the Children’s Hospital Research Institute of Manitoba, Research Manitoba, University of Manitoba, Health Science Foundation-Mindel and Tom Olenick Research Excellence Award in Immunology, and MITACS accelerate program.

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Authors and Affiliations

  1. Immunology Department, College of Medicine, University of Manitoba, 431 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada

    Nour Eissa, Laëtitia Kermarrec, Ahmed Y. Ali, Aaron Marshall & Jean-Eric Ghia

  2. Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada

    Nour Eissa & Jean-Eric Ghia

  3. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, OH, USA

    Hayam Hussein

  4. Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada

    Ahmed Y. Ali & Aaron Marshall

  5. Inserm UMR112, Biomatériaux et ingéniérie tissulaire, Institut Leriche 2éme étage, Hôpital Civil, Porte de l’Hôpital, BP 426, 67091, Strasbourg, France

    Marie-Helene Metz-Boutigue

  6. Metabolic Disorders and Complications, McGill University Health Centre-Research Institute, Departments of Medicine, Physiology, and Human Genetics, McGill University, Montreal, QC, Canada

    Geoffrey N. Hendy

  7. Internal Medicine Section of Gastroenterology, University of Manitoba, Winnipeg, MB, Canada

    Charles N. Bernstein & Jean-Eric Ghia

  8. IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada

    Charles N. Bernstein & Jean-Eric Ghia

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  1. Nour Eissa
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  2. Hayam Hussein
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  3. Laëtitia Kermarrec
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  4. Ahmed Y. Ali
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  6. Marie-Helene Metz-Boutigue
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  7. Geoffrey N. Hendy
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  8. Charles N. Bernstein
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  9. Jean-Eric Ghia
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Contributions

Conceived and designed the experiments: NE and JEG. Performed the experiments: NE. Analyzed and interpreted the data: NE and JEG. Revised the data analysis and interpretation: NE, CNB, JEG. Performed research: HH, LK, AA, AM, MM, and GH. Contributed reagents/materials/analysis tools: JEG. Wrote the paper: NE, JEG. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Jean-Eric Ghia.

Ethics declarations

This study was approved by the University of Manitoba Health Research Ethics Board (HS14878 [E]). Persons undergoing colonoscopy either with known IBD or without IBD gave consent for the collection of biopsies. Experiments were approved by the University of Manitoba Animal Ethics Committee (Protocol No. 15-010) and were conducted under the Canadian guidelines for animal research.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Eissa, N., Hussein, H., Kermarrec, L. et al. Chromogranin-A Regulates Macrophage Function and the Apoptotic Pathway in Murine DSS colitis. J Mol Med 96, 183–198 (2018). https://doi.org/10.1007/s00109-017-1613-6

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  • DOI: https://doi.org/10.1007/s00109-017-1613-6

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