The IL-17 subtypes can be produced by a number of different cell types including TH17 cells (Table 1).32,59 Importantly, while TH17 cells are highly noted in psoriasis pathogenesis, many other immune cells as well as epithelial cells can also potentially produce excess IL-17.
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
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
