Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

Abstract

The IL-17 cytokine family comprising IL-17A to IL-17F and receptor subunits IL-17RA to IL-17RE represents a genetically ancient intercellular network regulating local tissue homeostasis. Its pivotal role in antifungal defense and its central position in the pathogenesis of inflammatory diseases including psoriasis were discovered only relatively late in the early 2000s. Since the connection of dysregulated IL-17 and psoriasis pathogenesis turned out to be particularly evident, a number of monoclonal antibodies targeting IL-17 pathways have been approved and are used as first line treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis, and further agents are currently in clinical development.

Interleukin-17 pathway activation inEquus caballussupporting limb laminitis

“…Interestingly, several histomorphologic features of equine laminitis are similar to those described for both physiologic cutaneous wound-healing and select chronic auto-inflammatory skin conditions, including human psoriasis. Human psoriasis is a chronic, heterogeneous immune-mediated inflammatory disease with genetic and epigenetic triggers that activate pro- inflammatory pathways, including IL-17A (referred to hereafter as IL-17) [18; 20; 21], resulting in cutaneous and nail manifestations including aberrant epidermal and subungual keratinocyte activation, differentiation and proliferation, vascular disturbances and inflammation, as well as extracutaneous manifestations [22]. A causal role for IL-17-dependent inflammation in driving psoriasis is highlighted by the success of monoclonal antibody-based therapies that bind IL-17 and block signaling through the IL-17 receptor [18; 21; 23].…”

“…Human psoriasis is a chronic, heterogeneous immune-mediated inflammatory disease with genetic and epigenetic triggers that activate pro- inflammatory pathways, including IL-17A (referred to hereafter as IL-17) [18; 20; 21], resulting in cutaneous and nail manifestations including aberrant epidermal and subungual keratinocyte activation, differentiation and proliferation, vascular disturbances and inflammation, as well as extracutaneous manifestations [22]. A causal role for IL-17-dependent inflammation in driving psoriasis is highlighted by the success of monoclonal antibody-based therapies that bind IL-17 and block signaling through the IL-17 receptor [18; 21; 23]. Interestingly, a syndrome of psoriasis involving digits and nail beds, termed psoriatic onychodystrophy and psoriatic arthritis/dactylitis, includes lesions such as onycholysis, subungual acanthosis and hyperkeratosis, enthesitis and distal phalangeal osteolysis [24; 25].…”

“…Many of the changes listed above for human psoriasis have morphological similarities to equine laminitis and laminitis-associated distal phalangeal osteolysis [11]. IL-17 stimulated inflammation is also associated with a number of other human diseases, including rheumatoid arthritis, obesity-associated inflammation and cancer [19; 21; 26-29].…”

“…In human skin diseases and normal healing processes, both immune cells and keratinocytes respond to IL-17 directly via its receptor, a heterodimer of IL-17RA and IL-17RC (Fig 2; [18; 21; 30; 31]). Receptor activation results in increased expression of target genes either through enhanced translation or increased mRNA stability [21; 28; 33]. The cohort of target genes includes the ß defensins, with ß defensin 4 (human gene DEF4B ) ranking as the most highly upregulated gene in human keratinocytes treated with IL-17 [34].…”

“…ß defensin 4 (also known as human ß defensin 2) is a biomarker for psoriasis and its decline provides a quantitative measure of immunotherapy efficacy [35; 36]. Additional effectors include cytokines, chemokines, antimicrobial proteins and matrix metalloproteinases [18; 21; 28; 33] as summarized in Fig 2.…”