Interleukin-17 Links Inflammatory Cross-Talks Between Comorbid Psoriasis and Atherosclerosis

Abstract

Psoriasis is a chronic, systemic, immune-mediated inflammatory disorder that is associated with a significantly increased risk of cardiovascular disease (CVD). Studies have shown that psoriasis often coexists with atherosclerosis, a chronic inflammatory disease of large and medium-sized arteries, which is a major cause of CVD. Although the molecular mechanisms underlying this comorbidity are not fully understood, clinical studies have shown that when interleukin (IL)-17A inhibitors effectively improve psoriatic lesions, atherosclerotic symptoms are also ameliorated in patients with both psoriasis and atherosclerosis. Also, IL-17A levels are highly expressed in the psoriatic lesions and atherosclerotic plaques. These clinical observations implicit that IL-17A could be a crucial link for psoriasis and atherosclerosis and IL-17A-induced inflammatory responses are the major contribution to the pathogenesis of comorbid psoriasis and atherosclerosis. In this review, the current literature related to epidemiology, genetic predisposition, and inflammatory mechanisms of comorbidity of psoriasis and atherosclerosis is summarized. We focus on the immunopathological effects of IL-17A in both diseases. The goal of this review is to provide the theoretical base for future preventing or treating psoriasis patients with atherosclerosis comorbidity. The current evidence support the notion that treatments targeting IL-17 seem to be hold some promise to reduce cardiovascular risk in patients with psoriasis.

Keywords: IL-23 / IL-17 axis; atherosclerosis; cardiovascular disease; interleukin (IL)-17; interleukin (IL)-17A; psoriasis.

Figure 1

The roles of IL-17 in both psoriasis and atherosclerosis. The IL-17 family has six members (IL-17A to IL-17F), of which, IL-17A has the highest biological activity. Psoriatic lesions are characterized by high expression levels of IL-17A and IL-17F, which are believed to be responsible for tissue inflammation by recruiting neutrophils and forming micro abscesses on the sites. IL-17F acts in a manner similar to IL-17A in psoriatic lesions. Both IL-17A and IL-17C can aggravate psoriatic lesions and promote instability of atherosclerotic plaques. IL-17D has the highest homology with IL-17B, and the transcript levels of IL-17B and IL-17D are reduced in psoriatic lesions. However, the effects of IL-17B and IL-17D in atherosclerosis are still unknown. IL-17E expression is upregulated in psoriatic lesions, while IL-17E is protective against atherosclerosis. Red solid line: pathogenic role; Green solid line: non-pathogenic role; Gray dotted line: unknown function.

Figure 2

The IL-23/IL-17 axis in inflammation: Hypothetical mechanisms linking comorbid psoriasis and atherosclerosis. The shared molecular mechanisms, such as the IL-23/IL-17 inflammatory pathway, may exist in the pathogenesis of psoriasis and atherosclerosis. Stimulated keratinocytes and vascular endothelial cells will transfer signals to inflammatory cells (e.g., macrophages, dendritic cells, lymphocytes and monocytes) in skin epidermis or endothelium to release transforming growth factor (TGF)-β and inflammatory cytokines (e.g., IL-6, IL-21, IL-1β, IL-12, and IL-23). Thus, the inflammatory microenvironment emerges to stimulate the production of IL-17. IL-17 family includes 6 subtypes (IL17A-F), and the expressions of IL-17A and IL-17F are significantly elevated in the disease process. There are several types of IL-17-derived cells (e.g., innate lymphoid cells (ILCs), γ δ T cells, naïve T cells, mast cells, and neutrophils) and the main source of IL-17 is the differentiation of naive T cells into Th17 cells. Naive T cells can also be differentiated into Th1 cells that promote the production of IFN- γ and TNF-α to assist the IL-23/IL-17 axis in the pathogenesis of the diseases. Th17 cells also highly express IL-23R for IL-23 binding, which sustains IL-17 production and increases Th17 cell proliferation and survival. Th17 cell differentiation requires retinoid-related orphan receptor (ROR)-γt that cooperates with other transcription factors, including ROR-α, signal transducers and transcriptional activators 3 (STAT3) for resultant IL-17 production, which could further aggravate the inflammation on the epidermis and show proatherogenic effects on vascular endothelium. Current evidence tends to support the view that IL-17 exerts mainly pro-inflammatory role in the comorbid psoriasis and atherosclerosis.