The immunomodulatory functions of chromogranin A-derived peptide pancreastatin

Abstract

Chromogranin A (CgA) is a 439 amino acid protein secreted by neuroendocrine cells. Proteolytic processing of CgA results in the production of different bioactive peptides. These peptides have been associated with inflammatory bowel disease, diabetes, and cancer. One of the chromogranin A-derived peptides is ∼52 amino acid long Pancreastatin (PST: human (h)CgA_250-301, murine (m)CgA_263-314). PST is a glycogenolytic peptide that inhibits glucose-induced insulin secretion from pancreatic islet β-cells. In addition to this metabolic role, evidence is emerging that PST also has inflammatory properties. This review will discuss the immunomodulatory properties of PST and its possible mechanisms of action and regulation. Moreover, this review will discuss the potential translation to humans and how PST may be an interesting therapeutic target for treating inflammatory diseases.

Keywords: Chromogranin A (CgA); Inflammation; Macrophages; Pancreastatin (PST).

Fig. 1.

Mature human CgA (NM_001275) and its bioactive peptides. Human CgA is intra- and extracellularly cleaved by proteases including Convertase, Cathepsin L, Kallikrein, and Plasmin. Cleavage of CgA results in several bioactive peptides, including Vasostatin 1, Vasostatin 2, PST, WE14, CST, and Serpinin.

Fig. 2.

Predicted structure of CgA. The structure of CgA is predicted by AlphaFold. The Pancreastatin region is indicated in Red. N- and C-terminal cleavage sites of the Pancreastatin region are marked with a dotted line.

Fig. 3.

CgA sequence alignment. Mature (i.e., without signal sequence) forms of Cga from Homo sapiens (NM_001275), Mus musculus (NM_007693), Rattus norvegicus (NM_021655), Bos taurus (NM_181005), Sus scrofa (NM_001164005), Equus caballus (NM_001081814), Ovis aries (NC_056071), Canis lupus familiaris (NC_051812), Felis catus (NC_058373), Saimiri boliviensis (NW_024100921), Callithrix jacchus (NC_048392), Gorilla gorilla (NC_044616), Otolemur garnettii (NW_003852415), Ceratotherium simum simum (NW_004454204), Pan troglodytes (NC_036893), Macaca fascicularis (NC_052261), Macaca mulatta (NM_001278450), Papio anubis (NC_044982), Dasypus novemcinctus (NW_004489337), Cricetulus griseus (NW_003614307), Trichechus manatus (NW_004443981), Orcinus orca (NC_064560), Odobenus rosmarus divergens (NW_004450295), Tursiops truncates (NC_047035). Yellow shows an amino acid match between species. Sequences are aligned to mature hCgA using the MUSCLE method provided by SnapGene software.

Fig. 4.

Hypothesis of the immunomodulatory functions of PST. PST induces the production of pro-inflammatory cytokines in macrophages whereas CST induces the production of anti-inflammatory cytokines. Neuroendocrine cells and potentially also macrophages produce CgA that is cleaved intra- and extracellular by different proteases resulting in PST and CST. Pancreastatin reduces the expression of tight junction components resulting in the increased leakage of bacterial products or dietary fibers through the epithelial barrier, stimulating other immune cells like dendritic cells. CST can reverse this effect by increasing the expression of tight junction components in epithelial cells. Moreover, the release of CgA and CgA-derived peptides can also influence other immune- and epithelial cells. Figure created using BioRender.