The role of epigenetics and immunological imbalance in the etiopathogenesis of psoriasis and psoriatic arthritis

Abstract

Psoriasis (Ps) and psoriatic arthritis (PsA) represent a clinical and immunopathogenic continuum, called psoriatic disease, cumulatively affecting approximately 3% of the general population. Psoriatic disease is a chronic inflammatory disorder affecting the skin and musculoskeletal system. The immuno-pathogenesis is characterized by an activation of the TNF/IL-23/IL-17 cytokine axis, leading to an immunologic imbalance of T-cells resident in all affected tissues, mainly entheses. In the majority of cases, skin Ps predates rheumatological manifestations. Secondary to the higher incidence and the availability of mouse models, there is stronger data available on skin Ps, and data are, in most cases, relevant also to PsA. In a widely accepted model, environmental trigger factors like infections or trauma are capable of initiating an inflammatory cascade, ultimately creating a sustained state of chronic inflammation in genetically susceptible individuals. Besides well-known genetic susceptibility loci, epigenetic DNA modifications, which are associated with Ps development have been characterized recently and will be discussed in this article. The current evidence is promising in the possibility to provide new therapeutic avenues and fill the unmet need of patients, for whom current treatments either do not allow the disease to be controlled or must be continued for life.

Keywords: DNA methylation; IL17; IL23; Th17; chronic inflammation; histone modification; psoriasis; psoriatic arthritis.

Figure 1.

The proposed mechanisms of the immunological imbalance observed in psoriasis are summarized in the acute and chronic settings. In the acute phase of the disease, tissue damage induced, for example, by trauma or infection leads to the production of antimicrobial peptides by keratinocytes, particularly LL37. These peptides can form complexes with DNA or RNA molecules and, via toll-like receptor signaling, activate plasmacytoid dentritic cells (pDC), which produce type I interferons (IFN-α/β). Myeloid DCs are attracted and activated by IFN-α/β as well as from LL37/RNA complexes and secrete IL-12 and IL-23. They activate and induce helper T (T_H) cells to develop a T_H1 and T_H17 phenotype, respectively, and initiate the chronic phase of the disease characterized by sustained production of the indicated proinflammatory cytokines, leading to neutrophil recruitment, chronic skin inflammation, and the formation of psoriatic plaques.

Figure 2.

Epigenetic modifications involved in psoriasis immune-pathogenesis via activation of IL-17-producing cells. Hypoxia inducible factor 1α (HIF1α), induced by the hypoxic microenvironment, as well as IL-23 and TGF-β, cause hyperacetylation of histone H3 in the region of the miR-210 promoter. MiR-210 in turn targets the mRNA of STAT6 (Signal transducer and activator of transcription 6) and LYN (Lck/Yes novel tyrosine kinase), thereby inducing a T_H17 phenotype and IL-17 production (left panel). TNF-α signaling via phosphorylation of N-WASP (neural Wiskott-Aldrich syndrome protein) activates IL-23A expression via decreased H3K9 methylation of its promotor. IL-23 is the main inducer of IL-17 producing cells (right panel).