Potentiation of Psoriasis-Like Inflammation by PCSK9

Abstract

Psoriasis is a systemic inflammatory disease, associated with metabolic disorders, including high level of lowdensity lipoprotein. PCSK9, which promotes the degradation of low-density lipoprotein receptors and, therefore, the increased concentration of circulating low-density lipoprotein, is also involved in inflammation. This study aims to examine the role of PCSK9 in psoriasis and to investigate the potential of topically applying small interfering RNA targeting Pcsk9 as a psoriasis treatment. We investigated the expression of PCSK9 in lesions of psoriasis patients and imiquimod-induced psoriatic reactions in Pcsk9-knockout and Pcsk9 small interfering RNA-treated mice, and we also used cultured human keratinocytes to investigate the role of PCSK9 in regulating cell proliferation and apoptosis. We found that PCSK9 is overexpressed in psoriatic lesions and that suppressing Pcsk9 can decrease the inflammatory reaction induced by imiquimod treatment and inhibit hyperproliferation of keratinocytes. We also found that suppressing PCSK9 can significantly alter the cell cycle and induce apoptosis of human keratinocytes. Taken together, our findings indicate that PCSK9 plays an important role in psoriasis and may be a therapeutic target.

Methotrexate Decreases the Level of PCSK9—A Novel Indicator of the Risk of Proatherogenic Lipid Profile in Psoriasis. The Preliminary Data

“…In the present study, we found that serum PCSK9 concentration was significantly elevated in psoriatic patients compared to the controls. Luan et al suggested a possible role for PCSK9 in the course of this disease and further, proved that suppression of PCSK9 inhibits hyperproliferation of keratinocytes through inducing apoptosis [27]. According to these and our own results, we assume that PCSK9 is a novel biomarker of psoriasis, but not of its severity.…”

“…To our knowledge, there is only one paper investigating PCSK9 in psoriasis. Luan et al proved overexpression of PCSK9 in psoriatic lesions, indicating its important role in psoriasis, however the distinct relationship with lipid disorders should be further explored [27]. After considering these data, we maintained the thesis that PCSK9 seems to play a role in psoriasis and its association with the proatherogenic lipid profile, however further investigations are needed.…”

“…In 2018, in research conducted by Luan et al, the link between psoriasis and PCSK9 was proven. The authors found that PCSK9 is overexpressed in psoriatic-like lesions, provoked by imiquimod, in a mouse model [27].…”

“…Current literature has pointed that expression and release of PCSK9 depends on other chronic conditions including chronic kidney disease, hyperinsulinemia, hypothyroidism or non-alcoholic fatty liver disease (NAFLD) and also inflammation, which is a significant factor in psoriatic pathogenesis [24,25]. As well as NAFLD which shares similar pathogenetic pathways, particularly metabolic or immunological, with psoriasis, with co-occurence in up to 50% of the patients [26,27], there is increasing interest to comprehend whether PCSK9 has a positive or negative impact on the inflammation in chronic and autoimmune diseases [28,29].…”

Metabolic Syndrome and Skin Diseases

“…PCSK9 inhibitor is already approved to treat hyperlipoproteinemia (113, 114). Our previous study reported that suppressing PCSK9 inhibited the hyper-proliferation of keratinocytes and reduced the psoriasis-like inflammation via the NFκB pathway (115). Interestingly, according to the structure analysis, PCSK9 C-terminal cysteine-rich domain (CRD) reveals structural homology with resistin (116).…”