The Molecular Pathophysiology of Psoriatic Arthritis-The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome

Abstract

Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.

Keywords: chromatin; environment; epigenetic; inflammation; microbiota; nucleosome; psoriasis; psoriatic arthritis.

FIGURE 1

Psoriatic arthritis is a multifactor disease. Dendritic cells (DC) play a central role in the pathogenesis of psoriatic arthritis. DC activated by different stimuli produce and secrete IL-23 and IL-12 which further stimulate Th17, γδT cells and ILC3 and Th1 cells, respectively, leading to the production of inflammatory cytokines. Inflammatory cytokines can act by activating the JAK/STAT signaling pathway which regulates the expression of RANKL. RANKL binds to RANK activating osteoclast precursors. Environmental triggers such as changes in the microbiota, PAMPs (pathogen associated molecular patterns), and LPS can trigger the development of inflammatory cascades such as the MyD88/IRAK/TRAF6 pathway. Epigenetic mechanism, namely non-coding RNAs (e.g., MiR-146a), has been suggested as a critical link between environmental triggers and aberrant inflammatory responses. PsA genetic associations are highlighted with a red *.

FIGURE 2

The PsA multifactor model. Several questions remain unanswered regarding the impact of genetics, epigenetics, and environment/microbiota in the immunopathogenesis of PsA and the regulatory mechanism underlying the interaction between these factors.

FIGURE 3

Altered synovial vascularization in psoriatic arthritis is critical for the development of synovitis and inflammation which result in cartilage destruction and bone resorption. The PsA synovium is characterized by an increased vascularization that facilitates the infiltration of innate and effector immune cells. The increase of immune cells together with the proliferation of fibroblasts leads to a hypoxia environment that further stimulates angiogenesis and infiltration of more immune cells, inducing propagation of inflammation. The increased levels of VEGF, MMP-9, and EMMRPIN/CD147 observed in PsA synovium together with the several SNP and miRNA signatures associated with angiogenesis support the critical role of angiogenesis in the development of psoriatic arthritis.