Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis

Abstract

Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation. Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease. The discovery of IL-17-producing T cells in a mouse model of autoimmunity transformed our understanding of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis. Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations. Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed.

Figure 1.. Current pathogenic model of psoriasis.

Psoriasis initiation begins with environmental triggers and/or loss of tolerance, which leads to activation of plasmacytoid dendritic cells (pDCs) and IL-23-producing dermal DCs. Several pro-inflammatory DC cell populations present psoriasis autoantigens and trigger T17 cell polarization and clonal expansion. Activated T17 cells produce key cytokines including IL-17, IL-26, IL-29, and TNFα that act on epidermal keratinocytes to promote a feed-forward inflammatory response in skin. IL-17 acting alone or synergistically with TNFα induces expression of psoriasis-related genes in keratinocytes leading to epidermal hyperplasia and the production of antimicrobial peptides (e.g. hBD2, S100s, and LL37/cathelicidin). Keratinocyte-derived CCR20 recruits CCR6⁺ cells (IL-23-producing TIP-DCs and IL-17-producing T cells) to further promote inflammation. CXCL1/2/3/5/8 are also produced by keratinocytes and recruit neutrophils and macrophages into inflamed skin. IL-23 promotes the clonal expansion and differentiation of T22 cells that produce IL-22, which works together with IL-19/IL-36γ to alter the terminal differentiation and proliferation of keratinocytes. IL-12 produced by activated DCs as well as keratinocyte-derived CXCL9/10/11 promotes the influx of Th1 cells into lesional psoriatic skin. Type 3 innate lymphoid cells (ILC3) in the skin also produce IL-17 and IL-22, which contribute to the development of skin inflammation.

Figure 2.. Extended IL-12 Cytokine Family.

The IL-12 family, which includes IL-12, IL-23, IL-27, IL-35, IL-39, and IL-Y, is made up of heterodimeric cytokines that bind to their respective receptors to mediate inflammation. The different subunits forming each cytokine, as well as their corresponding receptor chains, STAT signaling pathways, and functional roles in psoriasis, are highlighted. Some cytokines can have opposing effects in the skin depending on the biological context, as indicated by an asterisk (*). The specific roles of IL-Y, IL-27, IL-35, and IL-39 in psoriatic disease have not been systematically studied