Tumor Necrosis Factor α
Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.34 In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.35
A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.36 Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.
IL-23/TH17 Axis
A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named TH17 cells. CD161 is considered a surface marker for these cells.40 Strong evidence for this IL-23/TH17 axis has been shown in mouse and human models as well as in genetic studies.
IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.3 It is required for optimal development of TH17 cells41 from a committed CD4+ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,44 and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.45 Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.3 Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,46-48 and the gene coding for the p40 subunit is associated with psoriasis.46,47
Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.42 IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,49 and psoriasis patients have elevated levels of IL-22 in the skin and blood.50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.52 IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,53 and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.54 IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),55 and it is, therefore, thought that TH17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.56-58 These cytokines released by TH17 cells in addition to those released by TH1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.3
New therapies have been developed to target the IL-23/TH17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.59 Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.60 Newer drugs targeting the IL-23/TH17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.