The role of endogenous double stranded RNA in psoriasis pathogenesis

Abstract

Psoriasis is a chronic relapsing inflammatory immune-mediated disease affecting the skin, joints and cardiovascular system. Due to its chronicity, disfiguration, and associated comorbidities, psoriasis has a great impact on patients’ quality of life. It is a consequence of environmental triggers like infection, obesity or smoking in genetically susceptible persons. Understanding the complex interplay between the adaptive and innate immune systems in psoriasis pathogenesis has led to a great improvement in disease therapy, however, the great inter-patient variation in the treatment response is still a problem. It has been reported that a type I IFN response is stimulated in psoriasis and treating hepatitis C patients with pegylated IFN-α exacerbates the pre-existing psoriasis. The main trigger of type I IFN are atypical nucleic acids which are usually of a viral source, however, viral infection is not a common predisposing factor for psoriasis. Recently, two research groups have shown that, in normal conditions, human cells generate endogenous dsRNA in the absence of viral infection. The cellular dsRNA can be from either nuclear (repetitive elements) or mitochondrial sources. These abnormal duplexes are subjected to many control mechanisms to prevent their accumulation and activation of the immune system. Any abnormalities in the regulatory mechanisms lead to an increase in the cytoplasmic dsRNA which in turn activates a group of proteins called pattern recognition receptors. These proteins will either activate apoptosis or initiate an inflammatory response mediated by type I IFN. In this study, I have investigated the role of endogenous dsRNA in psoriasis by examining the expression changes of dsRNA sources in psoriatic non-lesional and lesional skin. I have also examined the expression changes of the genes controlling dsRNA degradation in psoriasis. Type I interferon and interferon-stimulated gene expression were also examined as an indirect measure of dsRNA levels in psoriasis. Furthermore, the effect of narrow-band UVB, an antipsoriatic treatment, on dsRNA and its downstream signalling was also investigated. The results of this study didn’t show an obvious increase in neither nuclear nor mt-dsRNA formation, however, the control mechanisms like ADAR A to I editing (that degrades nuclear dsRNA), BAX-BAK pathway (controlling the cytosolic efflux of mitochondrial dsRNA) and mitophagy were greatly dysregulated in psoriatic lesional skin. These observations were associated with an increase in all dsRNA binding proteins with activation III of their downstream signalling. Additionally, the expression of most of interferon stimulated genes was enhanced in psoriatic lesional skin and the pathways controlling an anti-dsRNA response were among the top activated pathways in psoriasis. All these changes were associated with a decrease in mt-dsRNA formation 24h after NB-UVB irradiation. UV irradiation also reduced the mRNA levels of all dsRNA sensors and the protein level of one of these proteins (RIG-I). In conclusion, my findings showed a potential increase of dsRNA in psoriasis. This increase was partially reverted by NB-UVB irradiation indicating that dsRNA might be a target for antipsoriatic treatment. These findings are important for a better understanding of psoriasis pathogenesis and might lead to the introduction of new antipsoriatic therapy