The melanocortin system is a complex set of molecular mediators and receptors involved in many physiological and homeostatic processes. These include the regulation of melanogenesis, steroidogenesis, neuromodulation and the modulation of inflammatory processes. In the latter context, the system has assumed importance in conditions of chronic digestive inflammation, such as inflammatory bowel diseases (IBD), in which numerous experiences have been accumulated in mouse models of colitis. Indeed, information on how such a system can counteract colitis inflammation and intervene in the complex cytokine imbalance in the intestinal microenvironment affected by chronic inflammatory damage has emerged. This review summarises the evidence acquired so far and highlights that molecules interfering with the melanocortin system could represent new drugs for treating IBD.
The melanocortin system is a complex and phylogenetically ancient system of peptides, comprising α-, β- and γ-melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH), resulting from a common protein precursor, pro-opiomelanocortin (POMC). POMC is modified in the post-translational phase and provides precursor peptides (γ-MSH, ACTH, β-lipotropins) that, when adjusted by glycosylation, amidation and acetylation, provide active mediators. In particular, the α-melanotropin group is the product of the action of the precursor convertase 2 enzyme on ACTH as an enzyme substrate.
Molecules belonging to the melanocortin family can interact with varying degrees of affinity at five melanocortin receptors identified and characterised to date (i.e., MC1–5R). They show different topographical features but particularly nuanced receptor affinity characteristics, except for MC2R, which, on the contrary, seems to offer an exclusive affinity towards ACTH. These receptors bind various agonists with different affinities, and of these, Nle-D-Phe47 (NDP)-α-MSH is among those with the greatest potency towards MC1R, MC3R, MC4R and MC5R compared with other agonists such as α-MSH, ACTH, β-MSH or γ-MSH. MC2R, on the other hand, recognises ACTH(1-24) and DPhe7-ACTH(1-24) as potent agonists.
The receptors are expressed in a tissue-dependent manner. In detail, the MC1R receptor is expressed in a wide range of cytotypes (fibroblasts, melanocytes, keratinocytes, neutrophils, monocytes, dendritic cells, B lymphocytes, gliocytes, endotheliocytes and neoplastic cells). It responds to ACTH and α-MSH and is mainly involved in eumelanin synthesis in melanogenesis by activating the enzyme tyrosinase. As stated before, MC2R, in contrast to the other receptors, shows a specific receptor affinity for ACTH and is mainly expressed in the adrenal cortex and adipocytes and is involved in steroid synthesis. MC3R has a widespread expression pattern in the central nervous system (CNS) and immune cells (predominantly B lymphocytes and macrophages) but is also expressed in the gut, heart and placenta. It has a role mainly related to metabolic control. MC4R is the most highly expressed receptor in the CNS and is involved in regulating energy homeostasis and feeding behaviour, and ultimately, a role in neuroprotection has also been described. Finally, MC5R has a predominantly ubiquitous distribution and has been linked to the immunomodulation of B/T lymphocyte responses and the control of exocrine glandular secretions.
Together, MCRs belong to the macrofamily of G-protein-coupled receptors with seven transmembrane segments, for which several ligands have also been identified.
It has been repeatedly stigmatised that the melanocortin system may play a pivotal role in inflammatory bowel diseases (IBD). Therefore, this review aims to present studies that have evaluated the possibility of modulating the system regarding the pathogenesis and therapy of IBD, with a particular focus on melanocortin receptors.
The pathogenesis of IBD is particularly complex and far from fully elucidated. It is thought to be the product of the interaction between several pathogenic elements, including the intestinal epithelium, DNA-related factors (genetic and epigenetic), the intestinal mucosal system and the gut microbiota. In addition, psychopathological aspects have also been called into question, both as an epidemiological element of a high prevalence of mood disorders in patients with IBD (even in the absence of disease activity) and pathogenesis.
The mucosal immune system, however, plays a key role. In detail, mucosal-activated macrophages can produce large amounts of tumour necrosis factor (TNF), interleukin (IL) 6, IL-12 and IL-23, known proinflammatory mediators. At the same time, neutrophils can degranulate the contents of their intracellular granules. Lymphocyte cells also play a role as dendritic cells, and their migration into the mesenteric lymph nodes can present antigens to CD4+ T lymphocyte cells, inducing the proliferation of T helper lymphocytes (i.e., T H 1 or T H 17), which produce additional proinflammatory mediators (i.e., interferons, IL-17A, IL-17F, IL-22).
In the intestinal microenvironment of IBD, dysregulation of cytokines, the production of which is strongly controlled by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), is therefore particularly evident. This production is dramatically altered and imbalanced in favour of increased production of proinflammatory cytokines (such as TNF-α, IL-1 and IL-6), as evidenced by the increased concentration of NF-κB p65 in intestinal macrophages within intestinal biopsies from patients with IBD. The expression levels of this molecule also correlated directly with disease severity. NF-κB is activated in macrophages and epithelial cells of the inflamed intestinal mucosa. Among the previously mentioned cytokines, TNF and IL-1 activate metalloproteinases responsible for mucosal tissue damage and promote the differentiation of lymphocytes in the T H 1 direction.
The production of TNF in all these processes has thus gained prominence in the development of biological agents directed towards IBD in both Crohn’s disease (CD) and ulcerative colitis (UC) to the extent that anti-TNF (i.e., infliximab, adalimumab, golimumab) are still among the biologics of first choice in the therapeutic management of IBD and related major extraintestinal manifestations.
The direct role of melanocortins in the regulation of inflammatory processes has emerged from their potential to inhibit the family of NF-κB involved in the transcriptional regulation of many genes involved in the synthesis of cytokines (especially TNF) and related receptors, chemokines and adhesion molecules.
NF-κB can exert its activity in the presence of an adaptor that gives it the potential to activate the transcriptional process (activating domain). However, some proteins in this family, such as NF-κB1,2, lack this domain. They, therefore, reside in the cytoplasm, connected to an inhibitor molecule, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkBα). IkBα can be degraded, for example, by activating a series of receptors of the inflammatory system (such as TNFR, TLR, IL-1R), which, by promoting its degradation, allow NF-κB to translocate within the nucleus and act as a transcription factor.
NF-κB plays a role in both innate and acquired immunity. For example, it can be induced by toll-like receptors if they use myeloid differentiation primary response gene 88 (MyD88) as an adaptor. All toll-like receptors (TLR 1-9) are potential activators of MyD88, except for TLR3.
α-MSH is a 13-amino-acid neuroendocrine peptide that may play a vital role in these processes. For example, it may be responsible for downgrading NF-κB and inhibiting IL-8 within endotoxin-stimulated monocytes and tumour necrosis factor (TNF).
The effects of α-MSH are also exerted in the lymphocyte population. Evidence has shown its potential to induce immunological tolerance mechanisms and promote the development of CD4+ CD25+ T-regulatory lymphocytes. These regulatory T cells require antigen recognition for activation, but through nonspecific TGF-β1-mediated mechanisms, they can suppress other effector T cells, thus exhibiting immunomodulatory action. Furthermore, several cytokines such as IL-2, IFN-γ and IL-10 are under the regulation of α-MSH within antigen-induced cell proliferation. Interleukin-10 inhibits other proinflammatory cytokines such as IL-2, IFN-γ and TNF-α, and α-MSH has been shown to reduce the antigen-induced proliferation of splenic cells and nonregulatory CD4+-CD25- lymphocytes. Indeed, it appears that α-MSH may mediate the induction of TGF-β-producing T cells and suppressing the production of IFN-γ.
IBD has also been associated with TGF-β signalling. It has emerged from genome-wide association studies how certain gene variations in TGF-β may be related to an increased risk of IBD onset and how TGF-β1 deficiency is associated with very-early-onset IBD.
Furthermore, among the numerous pathways activated by α-MSH is the Janus kinase pathway, which has been extensively studied in IBD. In detail, it was found that α-MSH, by binding its MC5R receptor in Ba/F3 lymphocytes, activates the JAK2 pathway.
To understand the system’s potential in IBD, it is necessary to weigh the possibi
