Major Role of the IL17/23 Axis in Psoriasis Supports the Development of New Targeted Therapies.

Hélène Bugaut,Sélim Aractingi

doi:10.3389/fimmu.2021.621956

Abstract

Psoriasis is a frequent, chronic disease characterized by cutaneous inflammatory plaques and/or arthritis. It may be associated with few other diseases, mainly Crohn’s disease and metabolic syndrome. The medical and psychosocial burden of psoriasis remains high even since biological treatments arose, stressing that efforts to decipher its physiopathology are constantly needed. Tumor-necrosis factor α, interleukin (IL) 12 and IL17 have been previously associated with psoriasis and successfully targeted by monoclonal antibodies. IL17 in particular has been initially described as a T helper (Th) 17—produced cytokine, but it is now established that other cell types, such as γδ T lymphocytes, Mucosal-Associated Invariant T (MAIT) cells and Innate Lymphoïd Cells (ILC) 3 are also important sources of IL17 in the skin in response to inflammatory stimuli. Th17 phenotype has been shown to be stabilized by IL23, which is synthetized by macrophages and dendritic cells in response to Toll Like Receptors and C-type Lectin Receptors stimulation. Recent data also reported a crucial role for IL23 in MAIT17 and ILC3 homeostasis. Genome-wide association studies have found a significant link between IL23 receptor polymorphism and psoriasis susceptibility. IL23 signals through Janus kinase 2 and Tyrosine kinase 2, against which specific inhibitors are currently being tested. Monoclonal antibodies against IL17 and IL23 are only the beginning of a new avenue in psoriasis treatment. This review focuses on the molecular basis underlying IL23/IL17 axis blockade in psoriasis, and on future targets in this pathway.

Highlights

Psoriasis is a chronic inflammatory disease involving the skin and/or the joints
Skin lesions are featured by relapsing cutaneous erythro-squamous patches in its most frequent form, namely psoriasis vulgaris (PV)
ILC3 - like Th17 cells, IL17-producing Tgd cells and MAIT17 cells - are increased in blood and cutaneous lesions of psoriasis patients [70, 71]

Summary

Introduction

Psoriasis is a chronic inflammatory disease involving the skin and/or the joints. Psoriasis prevalence in adults ranges from 0.51 to 11.43% worldwide [1] but is mainly considered to affect 2–3% of the population, with similar frequency in males and females [2]. Various mutations activating the proinflammatory NFkB pathway downstream of IL17 receptor (IL17R), such as in TRAF3 Interacting Protein 2 (TRAF3IP2), which encodes ACT1, a protein that allows signal transduction from the IL17R and downstream activation of NFkB, in CARD14 (an activator of NFkB), and in TNFAIP3 (tumor necrosis factor alpha induced protein 3, called A20) and TNFAIP3 Interacting Protein 1 (TNIP1), have been associated with an increased risk of developing psoriasis by GWAS studies, in Asian and Caucasian populations [10, 12,13,14,15,16,17,18,19,20]. The vast majority of available genetic association studies highlight the role of the immune system in the pathophysiology of psoriasis.

Results

Conclusion