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Item does not contain fulltext, Catestatin (CST) is a bioactive cleavage product of the neuroendocrine prohormone chromogranin A (CgA). Recent findings show that CST can exert anti-inflammatory and antiadrenergic effects by suppressing the inflammatory actions of mammalian macrophages. However, recent findings also suggest that macrophages themselves are major CST producers. Here, we hypothesize that macrophages produce CST in an inflammation-dependent manner and thereby might self-regulate inflammation in an autocrine fashion. CST is associated with pathological conditions hallmarked by chronic inflammation, including autoimmune, cardiovascular, and metabolic disorders. Since intraperitoneal injection of CST in mouse models of diabetes and inflammatory bowel disease has been reported to be beneficial for mitigating disease, we posit that CST should be further investigated as a candidate target for treating certain inflammatory diseases.

Contains fulltext : 244568.pdf (Publisher’s version ) (Closed access), AIM: A 'leaky' gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease (IBD), irritable bowel syndrome, and celiac disease. 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. METHODS: Colon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analyzed by immunohistochemistry, Western blot, 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. RESULTS: Plasma levels of CST were elevated in IBD patients. CST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, (ii) elevated expression of Claudin 2, and (iii) gut inflammation. 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. CONCLUSION: The pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts by antagonizing PST.

Radboud University, 11 oktober 2021, Promotores : Figdor, C.G., Bogaart, G. van den Co-promotores : Christoffersson, G., Mahata, S., Contains fulltext : 236684.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 229312.pdf (publisher's version ) (Open Access), Major histocompatibility complex (MHC) molecules are well-known for their role in antigen (cross-) presentation, thereby functioning as key players in the communication between immune cells, for example dendritic cells (DCs) and T cells, or immune cells and their targets, such as T cells and virus-infected or tumor cells. However, much less appreciated is the fact that MHC molecules can also act as signaling receptors. In this process, here referred to as reverse MHC class I (MHC-I) signaling, ligation of MHC molecules can lead to signal-transduction and cell regulatory effects in the antigen presenting cell. In the case of MHC-I, reverse signaling can have several outcomes, including apoptosis, migration, induced or reduced proliferation and cytotoxicity towards target cells. Here, we provide an overview of studies showing the signaling pathways and cell outcomes upon MHC-I stimulation in various immune and non-immune cells. Signaling molecules like RAC-alpha serine/threonine-protein kinase (Akt1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor-kappaB (NF-kappaB) were common signaling molecules activated upon MHC-I ligation in multiple cell types. For endothelial and smooth muscle cells, the in vivo relevance of reverse MHC-I signaling has been established, namely in the context of adverse effects after tissue transplantation. For other cell types, the role of reverse MHC-I signaling is less clear, since aspects like the in vivo relevance, natural MHC-I ligands and the extended downstream pathways are not fully known.The existing evidence, however, suggests that reverse MHC-I signaling is involved in the regulation of the defense against bacterial and viral infections and against malignancies. Thereby, reverse MHC-I signaling is a potential target for therapies against viral and bacterial infections, cancer immunotherapies and management of organ transplantation outcomes.

Contains fulltext : 229361.pdf (publisher's version ) (Open Access), The contribution of dendritic cell (DC) antigen cross-presentation to the activation of CD8(+) T lymphocytes for immune defense against tumors, viruses, and intracellular pathogens has been recognized widely. Although originally thought to be an exclusive characteristic of DCs, recently also other immune cells, particularly macrophages, have been shown capable of cross-presentation. Here we provide an overview of in vitro and in vivo evidence on cross-presentation by macrophages. As we discuss, it is now firmly established that various types of tissue-resident macrophages are able to cross-present via similar cellular pathways as DCs. This is based on a wide range of antigens in macrophages from many different tissue origins such as blood, tumors, and lymphoid tissue. However, the physiological relevance of macrophage cross-presentation with potential contributions to activation of CD8(+) T lymphocytes is still mostly unknown. While cross-presentation by various types of proinflammatory macrophages might be involved in cross-priming of naive CD8(+) T lymphocytes, it might also be involved in local reactivation of memory and/or effector CD8(+) T lymphocytes. Moreover, cross-presentation by anti-inflammatory macrophages could be related to immune tolerance. Because cross-presentation promotes the initiation and potentiation of antigen-specific CD8(+) T lymphocyte responses, stimulating macrophages to cross-present antigen might be a promising strategy for antitumor or antiviral therapies.

Contains fulltext : 201259.pdf (publisher's version ) (Open Access)

Contains fulltext : 199976.pdf (publisher's version ) (Open Access), It is increasingly clear that inflammatory diseases and cancers are influenced by cleavage products of the pro-hormone chromogranin A (CgA), such as the 21-amino acids long catestatin (CST). The goal of this review is to provide an overview of the anti-inflammatory effects of CST and its mechanism of action. We discuss evidence proving that CST and its precursor CgA are crucial for maintaining metabolic and immune homeostasis. CST could reduce inflammation in various mouse models for diabetes, colitis and atherosclerosis. In these mouse models, CST treatment resulted in less infiltration of immune cells in affected tissues, although in vitro monocyte migration was increased by CST. Both in vivo and in vitro, CST can shift macrophage differentiation from a pro- to an anti-inflammatory phenotype. Thus, the concept is emerging that CST plays a role in tissue homeostasis by regulating immune cell infiltration and macrophage differentiation. These findings warrant studying the effects of CST in humans and make it an interesting therapeutic target for treatment and/or diagnosis of various metabolic and immune diseases.