The role of chromogranin-A in inflammatory bowel disease: clinical & experimental approaches

Thumbnail Image
Eissa, Nour
Journal Title
Journal ISSN
Volume Title
Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the gastrointestinal tract and classified as Crohn’s disease (CD) and ulcerative colitis (UC). IBD is characterized by altered functions of macrophages and intestinal epithelial cells. Dextran sulfate sodium (DSS)- and 2,4-Dinitrobenzenesulfonic acid (DNBS)-induced colitis are experimental animal models that mimic UC and CD. For the first time, we determined the stability of reference genes in mice treated with DSS or DNBS and highlighted the importance of the appropriate choice of reference genes to ensure adequate normalization of RT-qPCR data. We reported that TATA-box-binding protein (Tbp) and eukaryotic translation elongation factor 2 (Eef2) were reference genes of choice instead of commonly used glyceraldehyde-3-phosphate dehydrogenase (Gapdh) and β-actin (Actb), which were not recommended. Chromogranin-A (CHGA) is secreted by enterochromaffin cells and is elevated in IBD patients. Chromogranin-A is cleaved into several bioactive peptides that regulate several biological functions. However, the role of chromogranin-A and its derived peptides in IBD remains unclear. Thus, we investigated the functions of chromogranin-A and its derived peptides in IBD. Chromofungin (CHR: CHGA47-66) is a short CHGA-bioactive peptide involved in immune regulation. We demonstrated that Chromofungin, which encodes by CHGA exon-IV, is decreased in active UC patients and correlated negatively with classically activated macrophages (M1) and nuclear transcription factor kappa B (NF-κB) activation markers, while it is correlated positively with alternatively activated macrophages (M2) and epithelial homeostasis markers. Chromofungin treatment decreased the severity of DSS-induced colitis through a decrease in M1 and NF-κB activation, and an enhancement of M2 and epithelial activation markers. In parallel, we found that chromogranin-A was elevated in patients with active UC and associated with an increase in M1 activity and epithelial apoptosis, and a decrease in M2 mediators. Deletion of chromogranin-A protected against DSS-induced colitis through the modulation of macrophages and epithelial cells functions via the caspase-3/p53 pathway. Amelioration of colitis in Chga-knockout mouse allowed us to determine if some of the CHGA-derived peptides could enhance the inflammatory cascades. We found that Pancreastatin (PST: CHGA273-301), which encodes by CHGA exon-VII, is increased in UC patients and correlated positively with M1 activity, while it is correlated negatively with M2, STAT3, and epithelial homeostasis. Administration of Pancreastatin exacerbated the severity of colitis in Chga-/- and Chga+/+ mice through an amplification of M1 activity by suppressing the phosphorylation of STAT3, restraining M2 activity and disturbing the epithelial homeostasis. To summarize, common reference genes are not recommended two animal models of IBD. Chromogranin-A plays a significant role in IBD; Chromofungin has protective features, while pancreastatin has detrimental effects during acute inflammation. Chromogranin-A, Chromofungin, and Pancreastatin appear as novel regulatory biomarkers and mediators in IBD, suggesting their potential for developing novel therapeutic strategies in IBD.
Gut Hormones, Macrophages, Colitis, Apoptosis, Mucosal Drug Action, Intestinal Epithelial Cells, Wound Healing, STAT3
Eissa, N., Hussein, H., Wang, H., Rabbi, M. F., Bernstein, C. N., & Ghia, J.-E. (2016). Stability of Reference Genes for Messenger RNA Quantification by Real-Time PCR in Mouse Dextran Sodium Sulfate Experimental Colitis. PloS one, 11(5), e0156289.
Eissa, N., Kermarrec, L., Hussein, H., Bernstein, C. N., & Ghia, J.-E. (2017). Appropriateness of reference genes for normalizing messenger RNA in mouse 2, 4-dinitrobenzene sulfonic acid (DNBS)-induced colitis using quantitative real time PCR. Scientific Reports, 7.
Eissa, N., Hussein, H., Kermarrec, L., Elgazzar, O., Metz-Boutigue, M.-H., Bernstein, C. N., & Ghia, J.-e. (2017). Chromofungin (CHR: CHGA47-66) is downregulated in persons with active ulcerative colitis and suppresses pro-inflammatory macrophage function through the inhibition of NF-κB signaling. Biochemical Pharmacology, 145, 102-113.
Eissa, N., Hussein, H., Kermarrec, L., Grover, J., Metz-Boutigue, M.-H. E., Bernstein, C. N., & Ghia, J.-E. (2017). chromofungin ameliorates the Progression of colitis by regulating alternatively activated Macrophages. Frontiers in Immunology, 8, 1131.