Update on psoriasis immunopathogenesis and targeted immunotherapy

Abstract

Over recent years, significant progress has been made in characterisation of the underlying pathogenic mechanisms in psoriasis, a common cutaneous disease that is associated with major systemic co-morbidity and reduced life expectancy. Basic science discoveries have informed the design of novel therapeutic approaches, many of which are now under evaluation in late-stage clinical trials. Here we describe the complex interplay between immune cell types and cytokine networks that acts within self-perpetuating feedback loops to drive cutaneous inflammation in psoriasis. Genetic studies have been pivotal in the construction of the disease model and more recently have uncovered a distinct aetiology for rare, pustular variants of psoriasis. The translation of mechanistic insights into potential advancements in clinical care will also be described, including several treatments that target the interleukin-23 (IL-23)/T17 immune axis.

Fig. 1

Schema for the initiation of a psoriatic skin lesion. Triggers such as trauma and infections lead to the release of self-DNA and self-RNA, which form complexes with LL37 and activate plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs), respectively. pDCs secrete type I interferons (IFN) and other cytokines including TNFα, IL-6 and IL-1β, which promote the activation of mDCs. These antigen presenting cells release pro-inflammatory cytokines that drive T cell-mediated inflammation and keratinocyte activation and proliferation. This promotes the recruitment and activation of further inflammatory cells such as neutrophils and macrophages, contributing to the formation of an inflamed cutaneous plaque. AMPs antimicrobial peptides

Fig. 2

Schema of the contribution of T cell subsets to the pathogenesis of psoriasis. Activated myeloid dendritic cells (mDC) release cytokines that promote the differentiation of populations of resident T cells into Th22, T17 and Th1 cells. Cytokines secreted by these effector T cells stimulate keratinocytes, which promote the recruitment of other inflammatory cells such as neutrophils by release of chemokines. Activation of autocrine and paracrine feedback loops culminates in the development and maintenance of cutaneous inflammation. AMPs antimicrobial peptides, VEGF vascular endothelial growth factor

Fig. 3

The IL-23/T17 pathogenic axis is an important therapeutic target in psoriasis. IL-23 is a heterodimeric cytokine that is released by dendritic cells and binds to the IL-23 receptor (IL23R) on T17 cells. IL-23R is associated with Jak2 and Tyk2, which activate STAT3 molecules, resulting in the upregulation of IL-17A. Engagement of IL-17R on keratinocytes with IL-17A homodimers or IL-17A/IL-17F heterodimers induces the activation of NF-κB dimers, which translocate to the nucleus and drive the transcription of pro-inflammatory cytokines, chemokines and antimicrobial peptides. Numerous genes (yellow) encoding proteins involved in the IL-23/T17 pathway have been shown by genome-wide association studies to confer psoriasis susceptibility. Following activation of IL-17R, ACT1 (encoded by TRAF3IP2) interacts with TRAF proteins and the IκB kinase complex (IKK). IKK subsequently phosphorylates the inhibitory proteins IκB (IκBα is encoded by NFKBIA), which normally form cytoplasmic complexes with NF-κB. Once phosphorylated, IκB is subject to ubiquitin-induced proteasomal degradation, resulting in the nuclear translocation of NF-κB. Further, the protein products of TNFAIP3 and TNIP1, A20 and ABIN1, respectively, physically interact to enable the ubiquitin-mediated destruction of NEMO (a regulatory protein that activates IKK). Several medications for psoriasis (red) target components of the IL-23/T17 immune axis