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

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 96; no. 2; pp. 183 - 198
• Main Authors: Eissa, Nour, Hussein, Hayam, Kermarrec, Laëtitia, Ali, Ahmed Y., Marshall, Aaron, Metz-Boutigue, Marie-Helene, Hendy, Geoffrey N., Bernstein, Charles N., Ghia, Jean-Eric
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2018; Springer Nature B.V; Springer Verlag
• Subjects: Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biotechnology; Caspase; Caspase-3; Cell activation; Cells, Cultured; Chromogranin A - genetics; Chromogranin A - metabolism; Clonal deletion; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Colon; Colon - metabolism; Colon - pathology; Cytokines; Dextran; Dextran Sulfate; Epithelial cells; Functional plasticity; Human Genetics; Humans; Immunomodulation; Inflammatory bowel disease; Inflammatory bowel diseases; Internal Medicine; Intestine; Life Sciences; Macrophages; Macrophages - metabolism; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Original Article; p53 Protein; Rodents; Sodium; Sulfates; Ulcerative colitis; Vascular Endothelial Growth Factor A - metabolism; Angiogenesis; Mucosal drug action; Gut hormones; Neuroendocrine cells; IBD; Enterochromaffin cells; Mucosal healing
• ISSN: 0946-2716; 1432-1440; 1432-1440
• DOI: 10.1007/s00109-017-1613-6

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.