Catestatin as a Target for Treatment of Inflammatory Diseases

Abstract

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.

Keywords: anti-inflammatory; catestatin; chromogranin A; immune modulation; inflammatory disease; macrophages.

Figure 1

Chromogranin A and its bio-active peptides. Cleavage of CgA gives rise to six known biological active peptides: vasostatin (Orange; hCgA₁₋₇₆), which has anti-adrenergic and anti-angiogenic functions (–57); Chromofungin (Yellow; hCgA₄₇₋₆₆) has antimicrobial effects as well as effects on innate immune regulation; pacreastatin (Purple; PST; hCgA_250−301), which has anti-insulin functions (42, 58, 59); WE-14 (green; hCgA_324−337), which acts as an autoantigen for the highly diabetogenic CD4⁺ T cell clones (–62); CST (Red; hCgA_352−372), which has pro-insulin, anti-obesigenic (63), pro-angiogenic (64, 65), anti-adrenergic, anti-hypersensitive (–68), cardiomodulatory (, –74) and anti-inflammatory functions (, , , –78); serpinin (blue; hCgA_402−439), which is pro-adrenergic and regulates granule biogenesis and acts as a myocardial ß agonist (79, 80).

Figure 2

Model of the suppressive effects of CST on inflammation. (A) Inflammatory state. High plasma levels of CRP (yellow) are present in an inflammatory state. Due to the presence of chemokines (CCL2) and upregulation of integrin ligands [ICAM-1 (green) and VCAM-1 (blue)] on the endothelial cells (orange), increased monocyte (purple) infiltration is present at the inflammation site. An inflammatory environment (red) is created by the upregulation of pro-inflammatory markers (F4/80, Itgam, Itgax, NOS2, MARCO, iNOS, MCP1) in macrophages (blue). The production of inflammatory cytokines is also increased (TNF-a, IL-1β, IL-6, IFN-γ) and infiltration of CD8⁺ T cells occurs. (B) CST treated state. Treatment with CST (light blue) results in lower levels of circulating CRP (78, 120) and reduced expression of integrin ligands (36). Monocyte infiltration is reduced (36, 75, 78, 121) and macrophages are polarized toward an anti-inflammatory phenotype, characterized by upregulation of anti-inflammatory markers [MRC1, ARG1, YM1, Mg11, Mgl2, Clec7a (36, 75, 121)] and increased production of IL-10 and IL-4 (75, 121). Moreover, expression of pro-inflammatory genes and cytokines are reduced (36, 75, 78, 121). There will be no infiltration of CD8⁺ T cells and Tregs might be present. Together, this contributes to an anti-inflammatory environment (green) and improved tissue architecture (36, 78, 121).