The Role of Alpha-MSH as a Modulator of Ocular Immunobiology Exemplifies Mechanistic Differences between Melanocortins and Steroids

Abstract

Melanocortins are a highly conserved family of peptides and receptors that includes multiple proopiomelanocortin-derived peptides and five defined melanocortin receptors. The melanocortins have an important role in maintaining immune homeostasis and in suppressing inflammation. Within the healthy eye, the melanocortins have a central role in preventing inflammation and maintaining immune privilege. A central mediator of the anti-inflammatory activity is the non-steroidogenic melanocortin peptide alpha-melanocyte stimulating hormone. In this review we summarize the major findings of melanocortin regulation of ocular immunobiology with particular interest in the ability of melanocortin to induce immune tolerance and cytoprotection. The melanocortins have therapeutic potential because their mechanisms of action in regulating immunity are distinctly different from the actions of steroids.

Keywords: alpha-MSH; eye; glucocorticoids; melanocortins.

FIGURE 1

Effects of different melanocortin receptors on immune activity. Through MC1r, MC3r, and MC5r, α-MSH suppresses inflammation and promotes the activation of anti-inflammatory activity and regulatory immunity. In macrophages, through MC1r and MC3r, α-MSH mediates alternative activation by which the macrophages suppress inflammation.^, Through MC5r, α-MSH mediates the activation of suppressor cell activity in macrophages that suppresses effector T cell activation and viability.^, Through MC5r on T cells, α-MSH promotes the activation of regulatory T cell activity and the suppression of effector T cells.^, In addition, through MC5r, α-MSH induces antigen presenting cells to promote activation inducible Treg cells^, (see Figure 2). Ag, antigen; LPS, lipopolysaccharide; MØ, macrophage.

FIGURE 2

Melanocortin-driven induction of autoantigen-specific protective immunity. Self-resolution or α-MSH treatment of experimental autoimmune uveitis in mice is followed by the induction of autoantigen-specific Treg cells that provide resistance to the recurrence of uveitis.^, This is driven by the action of α-MSH, through MC5r on macrophages, to induce antigen presenting activity that counter-converts autoantigen-specific effector T cells into inducible Treg cells.^, α-MSH upregulates APC generation of adenosine and expression of PD-L1. This process requires autoantigen-specific effector T cells expressing the adenosine 2A receptor. Ag, antigen, CD39, ecto-nucleoside triphosphate diphosphohydrolase 1; CD73, ecto-5′-nucleotidase; MHC II, major histocompatibility class II antigen; TCR, T-cell receptor.

FIGURE 3

Effects of α-MSH on uveitis and retinal cell health. Therapeutic application of α-MSH has the potential to suppress inflammation, induce immune tolerance, and promote retinal cell survival (see text). α-MSH can directly influence immune cells through their expression of melanocortin receptors to suppress activation of effector T cells (Th1, Th17 cells), while promoting iTreg cell activation. In macrophages, α-MSH suppresses production of proinflammatory cytokines and promotes antigen presenting activity that converts effector T cells into functional iTreg cells. In addition, RPE and photoreceptors express melanocortin receptors through which α-MSH promotes cell survival. EC, endothelial cell; IL-1β, -6, -12; interleukin-1beta, -6, -12; iTreg: inducible Treg cells; RPE, retinal pigment epithelial cells; PR, photoreceptor cell; ROS, reactive oxygen species; Th: T helper cells; TNFα; tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor.