Various therapies have been used to target IL-17. Some of these therapies target the IL-17A subtype while others target the IL-17 receptor. Receptor antagonism, in agents such as brodalumab, has different implications to cytokine antagonism in that more than one IL-17 subtype will be inhibited. In this section, we discuss not only cytokines IL-17A and IL-17F but also other cytokines such as IL-17C that are being studied in psoriasis pathogenesis.
IL-17A in Psoriasis Pathogenesis and Therapies That Target IL-17A
In psoriasis, IL-17A is elevated 28-fold compared to non-lesional skin.54 The primary function of IL-17A is in the recruitment of neutrophils, providing immunity to extracellular pathogens, and the activation of keratinocytes.16,56 IL-17A primarily induces these functions through keratinocytes, endothelial cells, and innate immune cells.18 In keratinocytes, IL-17A induces the production of antimicrobial peptides, proinflammatory cytokines and chemokines, and pro-proliferative cytokines.16,18,24,56,60 Activation of keratinocytes is crucial in the pathology of psoriasis as this propagates the cytokine cascade and leads to the formation of plaque psoriasis.18 In endothelial cells, IL-17A induces tissue inflammation and procoagulant activity via increased IL-6, IL-8, and intracellular adhesion molecule-1, which may attribute to cardiovascular comorbidities associated with psoriasis.18,61 In innate immune cells, IL-17A acts to recruit neutrophils and has proinflammatory effects on antigen-presenting cells.16,56,62 IL-17A binds to IL-17RA and IL-17RC, with a 50% homology to IL- 17F.16,63 Compared to IL-17F, IL-17A has a stronger binding affinity to these receptors and, therefore, has a greater transductional power. IL-17A can also present as a homo- or heterodimer.16,63
IL-17A is produced by many immune cells other than TH17 cells.16 These immune cells include innate lymphoid cells (ILCs), mast cells, neutrophils, CD8+ T cells, natural killer (NK) cells, natural killer T (NKT) cells, and lymphoid tissue inducer (LTi) cells.16 In fact, histological examination of lesional psoriatic skin shows that most IL-17A is expressed by neutrophils and mast cells; and IL-17A positive T cells such as TH17 are scarce.17,55,64
Two FDA-approved biologic therapies, secukinumab and ixekizumab, bind to the IL-17A subunit, thereby blocking two of the five IL-17 isoforms (AA and AF) (Figure 2). These agents offer therapeutic benefit through the normalization of dysregulated immune mediators and their genetic expression.26,65–68
IL-17F in Psoriasis Pathogenesis and Therapies That Target IL-17F
In psoriatic lesions, IL-17F is elevated by 33-fold compared to non-lesional skin and is, therefore, more elevated than IL-17A.54 Similar to IL-17A, the primary function of IL-17F in psoriasis is in the recruitment of neutrophils and providing immunity to extracellular pathogens.16,56 Additionally, IL-17F can act synergistically with TNF-α and IL-17A.69–71
IL-17F binds to the same receptors as IL-17A, IL-17RA, and IL- 17RC, with a 50% homology.16,63 IL-17F can also present as a homo- or heterodimer.16,63 IL-17F is produced by many of the same cells as IL-17A (Table 1).16