Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by an impaired skin barrier function associated with immune response abnormalities. It is a disease with increasing incidence and manifestations that can significantly affect the patient’s quality of life(1). Recent data show that AD affects worldwide 15-30% of children and 2-10% of adults. Being a component of the allergic march, patients with atopic dermatitis can develop asthma and allergic rhinitis in evolution, thus substantially impacting weight and psychomotor development and, subsequently, reflecting on the child’s social relationships. However, the therapeutic possibilities are limited, especially for the moderate and severe forms of the disease(2).
There are cases of severe diseases that do not improve with conventional therapy. For that reason, some cases of AD need targeted therapies(3-5).
It is known that the immune system is involved in the pathogenesis of atopic dermatitis. Interleukins are thought to play an essential role in triggering immune reactions and clinical manifestations. Several interleukins and their role in the pathogenesis of AD have been studied, but the mechanism is complex and incompletely elucidated(6,7).
It is believed that the immune response by the activation of T lymphocytes is involved in the lesion mechanism. Th1 and Th2 lymphocytes contribute to the initiation and maintenance of skin lesions. There are studies in which it has been observed that patients with atopic dermatitis have a Th1/Th2 imbalance in favor of Th2. Th2 lymphocytes, by synthesized cytokines, regulate immunoglobulin E production, reduce the expression of antimicrobial peptides from keratinocytes and stimulate epidermal hyperplasia(8,9).
Cytokines play an essential role in the pathogenesis of AD. There are many cytokines involved in the proinflammatory process of atopic dermatitis. Of these, interleukin-31 (IL-31) and interleukin-33 (IL-33) are considered novel cytokines. Data showed that, in many cases diagnosed with AD, the expression of IL-31 and IL-33 correlate with disease severity.
IL-31 represents a cytokine produced by CD4+ T helper cells and mast cells, and its secretion depends on IL-4. It is proven that IL-31 exerts its action on fibroblasts and eosinophils. The most acute effects of IL-31 action include proinflammatory cytokines production, cellular differentiation and proliferation, and tissue remodeling(10).
IL-31 signals through a complex receptor consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). The components of the IL-31 receptor are expressed on keratinocytes and activated monocytes(11).
It has been shown that staphylococcal enterotoxin B increases IL-31 in peripheral mononuclear cells. The stimulation of histamine receptor 4 associated with staphylococcal enterotoxin B may occur due to IL-31 mRNA expression(12).
Interleukin IL-31 in atopic dermatitis
The role of IL-31 in the pathogenesis of atopic dermatitis is still being studied. The literature data indicated that IL-31 activation might be triggered directly by allergen stimulation. This fact has not yet been clarified. There is also the hypothesis that secondary factors could determine the expression of this cytokine. Although Th2 cells are one of the primary producers of IL-31, both Th1 and Th2 cytokines could take part in the IL-31 pathway(13).
Itch is the most distressing manifestation of AD. Chemical mediators of pruritus include endogenous and exogenous substances, such as histamine, 5-hydroxytryptamine, substance P, and proteases. The role of IL-31 and its receptor in itching was a carefully studied topic. In 2004, the pruritogenic action of IL-31 in mice was discovered. Recent studies show the involvement of IL-31 in the pathogenesis of pruritus in inflammatory skin diseases, including atopic dermatitis(14,15).
The serum level of IL-31 in patients with AD is higher than the serum level of healthy individuals. A few studies have identified a correlation between the IL-31 serum level and the severity of AD or itchy intensity. The serum level of IL-31 correlates with the disease activity of atopic dermatitis(16).
Byeon et al. showed that the serum levels of IL-31 were significantly higher in children with AD than in healthy children. The serum IL-31 is correlated with AD severity evaluated through the SCORAD index. The researchers obtained a correlation between IL-31 serum levels and blood eosinophilic inflammatory markers in this study(17).
Other authors have studied IL-31 levels in biopsy specimens of patients with atopic dermatitis. Nobbe et al. and Neiss et al. found increased mRNA levels of IL-31 in skin biopsy of AD patients, without a significant correlation with the atopic dermatitis severity(18,19).
IL-33 is a new cytokine, a member of the IL-1 cytokine family. Numerous cells, including the following, secrete this cytokine: dendritic cells, fibroblasts, osteoblasts, macrophages, adipocytes, endothelial cells, bronchial epithelium, and smooth muscle cells. Its secretion begins after the cell damage signal. There is a specific receptor for IL-33, namely the ST receptor. The immune cascade initiates after attaching IL-33 to this receptor(20).
IL-33 activates mast cells and basophils, and this leads to the overproduction of proinflammatory cytokines. At the same time, it is implicated in mast cell maturation and activation(21).
IL-31 induces a T helper type-2 inflammation. IL-31 has an essential role in the inflammation of allergic diseases mediated by eosinophils and basophils’ activation. The role of genetic variants of IL-33 and its receptor on allergic disease risk is a studied topic. Studies carried out in the Brazilian and Chinese populations demonstrate a relationship between the genetic variants of IL-33 and the development of asthma(22-24). We do not have enough data about the association of IL-33 polymorphism with the risk and severity of AD. More studies are necessary on this topic.
Interleukin-33 in atopic dermatitis
The role of IL-33 in AD pathogenesis was not clarified. This cytokine is secreted by damaged tissue or the site of inflammation. ST2, the IL-33 receptor, is expressed on Th2 cells, eosinophils and mast cells. By activating these cells, IL-33 promotes a Th2-type immune response. This receptor contributes to the secretion of some proinflammatory factors, including TNF alpha, IL-6 and leukotrienes. In the skin of patients with AD, the expression of IL-33 increases in keratinocytes, endothelial cells and fibroblasts(25).
The serum level of IL-33 in a patient with atopic dermatitis is higher than those without atopy. Some studies confirm the correlation between serum level of IL-33 and skin lesion severity(26-28).
In studies performed on patients with AD, the correlations between the serum level of IL-33 and other biomarkers were also evaluated. No significant correlation between the serum level of IL-33 and the serum level of IgE or peripheral eosinophils count was identified(25,26,28).
Studies on mouse models revealed an increased expression of IL-33 and ST2 in the skin of mice with filaggrin deficiency. This may indicate a relationship between IL-33 and epidermal barrier defects in patients with atopic dermatitis(28).
Most recent data showed that IL-33 and IL-31 link to each other in many patients with AD, and their expression correlates with skin lesion severity. In a patient with atopic dermatitis, the serum level of IL-33 increases due to skin damage. After its secretion, the immune cascade is initiated, inducing the augmentation of inflammatory cytokines. The IL-33 promotes the IL-4-dependent production of IL-31 by CD4+ Th cells(29,30).
In their study on mice (2016), Rizzo et al. showed that DNp63 regulates IL-33 and IL-31 signaling in atopic dermatitis(31). The results of this study indicate that the isoform DNp63, a family member p63, plays an essential role in keratinocyte activation in AD. The overexpression of DNp63 in the basal keratinocyte of mouse models’ epidermis gave rise to epidermal hyperplasia, low terminal differentiation, Th2 inflammation and elevated expression of inflammatory molecules. The study on the mouse model highlighted that DNp63 has a direct effect on IL-31 and IL-33 expression. Shortly after Np63 expression, an elevated level of Th2 cytokines was observed in the skin.
IL-31, IL-33 and new therapeutic targets
Topically applied emollients, corticosteroids and calcineurin inhibitors for skin inflammation are the first-line treatment for atopic dermatitis. Second-line therapies include phototherapy, systemic cyclosporine, and oral steroids. Target treatment is an essential goal of research on AD(32).
Many studies have shown that IL-31 is a cardinal pruritogenetic cytokine. We know that itching significantly affects the quality of life of the patient with AD(33). IL-31 and antibodies against IL-31 were extensively studied to identify targeted therapies for atopic dermatitis.
Nemolizumab is a humanized anti-human IL-31 antibody(34). A randomized, double-blind, phase II, long-term extension study was conducted in more countries by Kenji et al. to evaluate the effect of nemolizumab in adults with moderate-severe atopic dermatitis(35). The study showed that the subcutaneous administration of anti-IL-31-antibody improved pruritus, lesions and sleep disturbances in patients with AD versus placebo in the 12 weeks of the study. Being a pathology that can be severe in childhood, studies to evaluate the efficacy and effects of anti-IL-31 antibodies are required for different age groups.
Chen et al. investigated the role of IL-33 inhibition in adult patients with moderate to severe AD(36). Their results showed that, in patients with atopic dermatitis who received IL-33 antibody, the skin inflammation was reduced. More studies are needed to evaluate the effects of anti-IL-33 antibodies in patients with AD.
Role of IL-31 and IL-33
in extrinsic AD versus intrinsic AD
Depending on the total serum level of IgE, atopic dermatitis can be classified into two forms: intrinsic AD and extrinsic AD. Extrinsic atopic dermatitis is defined by an increased level of total IgE and specific IgE in environmental and food allergens. The intrinsic form is non-allergic(37). The two forms of atopic dermatitis have the same clinical phenotypes. Regarding the expression of cytokines, there may be differences between the two forms. Some studies have shown that patients with extrinsic atopic dermatitis have elevated serum levels of Th2 cytokines (IL-4, IL-5, IL-13, IL-31), while in the case of intrinsic forms, the expression of IL-4 and IL-13 is lower(38).
Suárez-Fariñas et al. showed a significant correlation between Th2 cytokine levels and disease severity in both intrinsic and extrinsic forms of AD in adults(39).
Regarding IL-33, the studies did not show a significant correlation with the serum level of IgE, but only with the severity of the lesions(25).
We have to apply targeted therapy in both forms, therefore establishing differences in cytokine expression is imperative.
Atopic dermatitis is not a life-threatening disease, but the pruritogenic character can significantly influence the quality of life. Evaluating cytokine expression in AD is essential for establishing disease severity markers and for identifying new therapies.
Each of the two cytokines presented, IL-31 and IL-33, has an essential role in atopic dermatitis’s pathophysiological mechanism, being involved in skin inflammation and pruritus.
The evaluation of the IL-31/IL-33 axis and a better understanding of the relationship between the two interleukins could provide essential data for establishing a combined therapeutic target.
It is essential to establish the differences in immune mechanisms of the two forms of atopic dermatitis in order to select the appropriate targeted therapy.
Conflict of interests: The authors declare no conflict of interests.