Psoriasis pathogenesis and the development of novel targeted immune therapies

Abstract

Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.

Keywords: IL-17; IL-23; Psoriasis; autoantigens; brodalumab; ixekizumab; psoriatic arthritis; secukinumab; tildrakizumab, guselkumab, and risankizumab.

Figure 1. IL-23/T17-mediated effects on epidermal keratinocytes in psoriatic skin

Schematic showing the broad downstream effects of increased IL-23 and IL-17 signaling on various immune cell populations and keratinocyte biology. Regulated by IL-23, the primary effects of IL-17 on keratinocytes include the indirect induction of epidermal hyperplasia via IL-19 and IL-36, upregulation of the innate immune response and antimicrobial peptides (e.g. hBD2, S100A7, and LL-37), epidermal recruitment of leukocyte subsets (e.g. neutrophils and myeloid dendritic cells/mDCs) via increased production of keratinocyte-derived chemokines, and transcription of multiple pro-inflammatory genes (e.g. TNF, IL-1β, IL-6, IL-8) that act synergistically with TNF to sustain the inflammatory events in psoriatic skin.

Figure 2. IL-17-driven initiation of feed forward inflammation in keratinocytes and the induction of psoriatic plaques

A working model of psoriasis showing the activation and upregulation of IL-17 in a Type 17 resident memory T-cell (Trm) in pre-psoriatic skin. The increased production of IL-17 results in activation of the IL-17 receptor (IL17R) on viable keratinocytes and a “feed forward” inflammatory response via activation of IL-17-induced transcription factors (e.g. CCAAT-enhancer-binding protein beta, C/EBPβ). This “feed forward” inflammatory response in keratinocytes is self-amplifying and promotes the development of mature psoriatic plaques via the recruitment of pathogenic immune cells and over-production of IL-17-induced keratinocyte-derived gene products (e.g. S100A7/8/9, human β-defensin 2/hBD2, lipocalin-2/LCN2, and CCL20), which are noticeably increased in the upper layers of the epidermis, and also epidermal hyperplasia. A granular layer can be absent in mature psoriasis lesions, leading to retained nuclei in surface corneocytes (i.e. parakeratosis).