Pancreastatin Reduces Alternatively Activated Macrophages, Disrupts the Epithelial Homeostasis and Aggravates Colonic Inflammation. A Descriptive Analysis

Nour Eissa; Omar Elgazzar; Hayam Hussein; Geoffrey N Hendy; Charles N Bernstein; Jean-Eric Ghia

doi:10.3390/biomedicines9020134

Pancreastatin Reduces Alternatively Activated Macrophages, Disrupts the Epithelial Homeostasis and Aggravates Colonic Inflammation. A Descriptive Analysis

Biomedicines. 2021 Feb 1;9(2):134. doi: 10.3390/biomedicines9020134.

Authors

Nour Eissa^{1

2

3

4}, Omar Elgazzar¹, Hayam Hussein⁵, Geoffrey N Hendy⁶, Charles N Bernstein^{3

4}, Jean-Eric Ghia^{1

2

3

4}

Affiliations

¹ Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.
² Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
³ Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.
⁴ The IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB R3A 1R9, Canada.
⁵ National Research Centre, Department of Parasitology and Animal Diseases, Veterinary Research Division, Giza 12622, Egypt.
⁶ Metabolic Disorders and Complications, McGill University Health Centre-Research Institute, Departments of Medicine, Physiology, and Human Genetics, McGill University, Montreal, QC H4A 3J1, Canada.

Abstract

Ulcerative colitis (UC) is characterized by modifying alternatively activated macrophages (AAM) and epithelial homeostasis. Chromogranin-A (CHGA), released by enterochromaffin cells, is elevated in UC and is implicated in inflammation progression. CHGA can be cleaved into several derived peptides, including pancreastatin (PST), which is involved in proinflammatory mechanisms. Previously, we showed that the deletion of Chga decreased the onset and severity of colitis correlated with an increase in AAM and epithelial cells' functions. Here, we investigated PST activity in colonic biopsies of participants with active UC and investigated PST treatment in dextran sulfate sodium (DSS)-induced colitis using Chga^-/- mice, macrophages, and a human colonic epithelial cells line. We found that the colonic protein expression of PST correlated negatively with mRNA expression of AAM markers and tight junction (TJ) proteins and positively with mRNA expression of interleukin (IL)-8, IL18, and collagen in human. In a preclinical setting, intra-rectal administration of PST aggravated DSS-induced colitis by decreasing AAM's functions, enhancing colonic collagen deposition and disrupting epithelial homeostasis in Chga^+/+ and Chga^-/- mice. This effect was associated with a significant reduction in AAM markers, increased colonic IL-18 release, and decreased TJ proteins' gene expression. In vitro, PST reduced Chga^+/+ and Chga^-/- AAM polarization and decreased anti-inflammatory mediators' production. Conditioned medium harvested from PST-treated Chga^+/+ and Chga^-/- AAM reduced Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins and increased oxidative stress-induced apoptosis and proinflammatory cytokines release. In conclusion, PST is a CHGA proinflammatory peptide that enhances the severity of colitis and the inflammatory process via decreasing AAM functions and disrupting epithelial homeostasis.

Keywords: alternatively activated macrophages; chromogranin-A; gut hormones; intestinal epithelial cells; macrophages; mucosal drug action; pancreastatin; proinflammatory peptides.

Grants and funding

395678/CAPMC/ CIHR/Canada