Christoffersson, G. | bioRxiv Science

bioRxiv2020

The anti-inflammatory peptide Catestatin blocks chemotaxis

Increased levels of the anti-inflammatory peptide catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlates with less severe outcomes in hypertension, colitis and diabetes. However, it is unknown how CST reduces the infiltration of monocytes and macrophages in inflamed tissues. Here, we report that CST blocks leukocyte migration towards inflammatory chemokines. By in vitro and in vivo migration assays, we show that although CST itself is weakly chemotactic, it blocks migration of monocytes and granulocytes to inflammatory attracting factor CC-chemokine ligand 2 (CCL2) and macrophage inflammatory protein 2 (MIP-2). Moreover, it directs CX3CR1+ macrophages away from pancreatic islets. These findings support the emerging notion that CST is a key anti-inflammatory modulator.

cell biology↗

bioRxiv2020

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

AimA leaky gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we show how pro-hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352-372), the most abundant CgA-derived proteolytic peptide, affect the gut barrier. MethodsColon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analyzed by immunohistochemistry, ultrastructural and flowcytometry studies. FITC-dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250-301). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients. ResultsCST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, and (ii) gut inflammation. Consistently, plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-knockout mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-knockout mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-knockout mice supplementation with CST and/or PST in CgA-KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability. ConclusionThe pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts via antagonizing the effects of PST.

physiology↗