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A Possible Role for IL-17A in Establishing Th2 Inflammation in Murine Models of Atopic Dermatitis

2014; Elsevier BV; Volume: 134; Issue: 8 Linguagem: Inglês

10.1038/jid.2014.141

1523-1747

Nikhil Dhingra, Emma Guttman‐Yassky,

Asthma and respiratory diseases

Atopic dermatitis (AD) is associated with the effects of T helper type 2 (Th2) and Th22 cytokines. Recent studies, however, have also implicated Th17 in acute AD. Functional studies of Th2 and Th22 cytokines revealed their roles in generating molecular changes during AD; IL-17A's role, however, has yet to be defined. The report by Nakajima et al. (this issue) begins to define that role by demonstrating IL-17A's ability to induce Th2 inflammation in acute disease. Atopic dermatitis (AD) is associated with the effects of T helper type 2 (Th2) and Th22 cytokines. Recent studies, however, have also implicated Th17 in acute AD. Functional studies of Th2 and Th22 cytokines revealed their roles in generating molecular changes during AD; IL-17A's role, however, has yet to be defined. The report by Nakajima et al. (this issue) begins to define that role by demonstrating IL-17A's ability to induce Th2 inflammation in acute disease. Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by acute and chronic stages. The pathogenesis of AD is still unclear; both immune- and barrier-driven mechanisms have been demonstrated in murine models and in human disease. AD has been recognized predominantly as a T helper type 2 (Th2)/Th22-centered disease (Guttman-Yassky et al., 2011Guttman-Yassky E. Nograles K.E. Krueger J.G. Contrasting pathogenesis of atopic dermatitis and psoriasis–part II: immune cell subsets and therapeutic concepts.J Allergy Clin Immunol. 2011; 127: 1420-1432Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). Lesional AD skin is characterized primarily by increased expression of Th2 cytokines and chemokines (IL-4/IL-13, chemokine (C-C motif) ligand (CCL)17, OX40), Th22-related markers (IL-22), as well as Th1- (chemokine (CXC motif) ligand (CXCL10)), Th17- (Elafin/PI3, CXCL1), and Th17/Th22-mediated S100 epidermal responses. Although the pathogenic role of Th17 in psoriasis is well established and supported by disease antagonism with anti-IL-17 biologics (i.e., brodalumab, ixekizumab, and secukinumab), its role in the pathogenesis of AD remains unclear. Although IL-17 is increased in skin and peripheral blood in patients with acute disease (Gittler et al., 2012Gittler J.K. Shemer A. Suarez-Farinas M. et al.Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.J Allergy Clin Immunol. 2012; 130: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar), IL-17 and its associated antimicrobial peptides are much lower than in psoriasis, possibly explaining the increased risk of infections in AD (reviewed in Guttman-Yassky et al., 2011Guttman-Yassky E. Nograles K.E. Krueger J.G. Contrasting pathogenesis of atopic dermatitis and psoriasis–part II: immune cell subsets and therapeutic concepts.J Allergy Clin Immunol. 2011; 127: 1420-1432Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). A recent study by our group compared non-lesional tissue with that of acute and chronic lesions from the same patient, which revealed increased expression of IL-17 and several associated markers (CCL20, PI3) in acute AD compared with non-lesional skin. Interestingly, levels remained insignificantly changed as disease progressed to the chronic stage (Gittler et al., 2012Gittler J.K. Shemer A. Suarez-Farinas M. et al.Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.J Allergy Clin Immunol. 2012; 130: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar; Figure 1). Obtaining a functional understanding for IL-17A in AD has remained elusive until now. In this issue, Nakajima et al., 2014Nakajima S. Kitoh A. Egawa G. et al.IL-17A as an inducer for Th2 immune responses in Murine AtopicDermatitis Models.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.51Abstract Full Text Full Text PDF Scopus (121) Google Scholar used two murine models of AD, including hapten-mediated induction and flaky-tailed mice with spontaneous lesions, in the setting of IL-17A deficiency to evaluate its role in disease pathogenesis. Using both models, Nakajima et al. (2014) demonstrated that IL-17A deficiency attenuated Th2 induction during the acute phase of inflammation, implicating IL-17A as an inducer or modifier that drives IL-17A T cells toward Th2 in the early inflammation of susceptible skin. The hapten-induced mouse model of AD relies on the concept that chronic hapten exposure across an impaired barrier establishes a pro-inflammatory milieu (the "hapten-atopy hypothesis"; McFadden et al., 2011McFadden J.P. Dearman R.J. White J.M. et al.The Hapten-Atopy hypothesis II: the 'cutaneous hapten paradox'.Clin Exp Allergy. 2011; 41: 327-337Crossref PubMed Scopus (35) Google Scholar) dominated by Th2 T cells, mimicking the inflammation in AD skin. The hapten model by Nakajima et al. (2014) may explain how an immune response to an external allergic agent, via IL-17A-mediated Th2 induction, ultimately polarizes toward the acute AD cytokine milieu that has been described previously. In addition, the demonstration by Nakajima et al. (2014) of similar immune findings in barrier-deficient mice with spontaneous AD-like lesions helps to bridge our understanding of why some patients develop lesions only in the setting of a sensitizer, whereas others develop them spontaneously. Their finding that contact allergen-triggered disease and barrier deficiency both result in similar IL-17A-mediated induction of Th2 inflammation may explain how this clinical phenomenon occurs. Interestingly, in a recent report, Newell et al., 2013Newell L. Polak M.E. Perera J. et al.Sensitization via healthy skin programs Th2 responses in individuals with atopic dermatitis.J Invest Dermatol. 2013; 133: 2372-2380Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar described the use of the potent hapten dinitrochlorobenzene to study contact sensitization in humans, revealing an interesting dichotomy between patients with AD and volunteers without AD. Those with a history of AD exhibited preferential Th2 induction, whereas those without AD exhibited a Th1 response primarily. Thus, it can be postulated that in human AD, an allergen penetrating across a defective barrier may trigger low-grade IL-17A release; with ongoing stimulation by chronic happen exposure, it may induce Th2-polarizing molecules (thymic stromal lymphopoietin, CCL17), promoting naïve T cells toward Th2 and establishing the predominant immune polarization of AD. Interestingly, a similar concept may be applied to the role of Staphyloccoccus aureus, another implicated extrinsic agent, in triggering AD exacerbations. S. aureus superantigens, like the haptens in the study by Nakajima et al. (2014), were also demonstrated to induce IL-17A expression (Boguniewicz and Leung, 2010Boguniewicz M. Leung D.Y. Recent insights into atopic dermatitis and implications for management of infectious complications.J Allergy Clin Immunol. 2010; 125: 4-13Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar), potentially suggesting a common molecular link between the two major external inducers of disease flares. The AD mouse models used by Nakajima et al. (2014) have several inherent limitations with respect to their translatability to humans. Specifically, at present, no single mouse model represents acute and chronic AD with true accuracy; rather, these models are able to represent select characteristics of the disease process and generate AD-like clinical and molecular inflammation. The murine contact hypersensitivity model, for instance, can only be induced via potent sensitizing agents such as dinitrochlorobenzene, which have an inherent irritating capacity and thus induce nonspecific immune activation (i.e., of the innate immune response) in addition to antigen-specific activation. Conversely, clinically relevant sensitizers that cause allergic contact dermatitis, and may trigger human AD, do not exhibit an initial irritant response, thus making it difficult to translate the generated immunological data fully to human models. Another important limitation relates to γδ T cells, which Nakajima et al. (2014) found to be the chief producers of IL-17A in their study; the role of these T cells in human IL-17 production is unknown at present, and thus it is unclear whether a similar mechanism may exist in humans. Only a few studies prior to those by Nakajima et al. (2014) evaluated the human effector interplay between IL-17A and the Th2 pathway, particularly in skin disease, and a select subset from other tissue types reported results contradictory to those in this study. One such work, by Xu et al., 2010Xu G. Zhang L. Wang D.Y. et al.Opposing roles of IL-17A and IL-25 in the regulation of TSLP production in human nasal epithelial cells.Allergy. 2010; 65: 581-589Crossref PubMed Scopus (71) Google Scholar, on cultured nasal epithelial cells revealed an inhibitory effect of IL-17A on thymic stromal lymphopoietin expression, whereas Th2-sourced IL-25 (also known as IL-17E) had the opposite effect. Studies in skin too have produced dissimilar results from those by Nakajima et al. (2014). Bogiatzi et al., 2012Bogiatzi S.I. Guillot-Delost M. Cappuccio A. et al.Multiple-checkpoint inhibition of thymic stromal lymphopoietin-induced TH2 response by TH17-related cytokines.J Allergy Clin Immunol. 2012; 130: e5Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar demonstrated, using human skin explants and cultured dendritic cells, that IL-17A induced marked decreases in thymic stromal lymphopoietin and Th2-related cytokine production. Eyerich et al., 2009Eyerich K. Pennino D. Scarponi C. et al.IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response.J Allergy Clin Immunol. 2009; 123: e4Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar complicated this picture further, postulating that IL-4 was capable of inhibiting the IL-17 pathway as well. A final point of consideration is revealed in recent studies that identified a subset of Th2 T cells capable of producing IL-17A itself. Wang et al., 2010Wang Y.H. Voo K.S. Liu B. et al.A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma.J Exp Med. 2010; 207: 2479-2491Crossref PubMed Scopus (333) Google Scholar demonstrated the presence of these IL-4- and IL-17-producing Th2 T cells in peripheral blood of allergic asthmatics. It can be postulated that IL-17A produced by these dual-function cells may signal back on naive T cells, augmenting Th2 activity. Interestingly, they reported that these cells could be stimulated to produce IL-17 by IL-1β, IL-6, and IL-21 but not by IL-23, suggesting a distinct mechanism from classical Th17-mediated release. The same study found that in murine models of allergic asthma, mice with allergen-specific IL-17-producing Th2 cells exhibited increased airway inflammation following allergen exposure, suggesting some correlation between clinical disease activity and stimulation of these IL-17-producing Th2 T cells. Similarly, in skin, Eyerich et al., 2009Eyerich K. Pennino D. Scarponi C. et al.IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response.J Allergy Clin Immunol. 2009; 123: e4Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar used eczema samples and identified that approximately one-third of IL-17-producing cells exhibited a concurrent Th0 or Th2 profile (both IL-4-producing without or with IFN-γ, respectively). Thus, additional studies, based on the work by Nakajima et al. (2014), will be required to evaluate the possibility that IL-17A is itself being sourced from a subset of Th2 T cells rather than from the classically presumed Th17 cells. AD research has recently entered a new era in which our collective understanding of the immune mechanisms driving disease has led to the development and testing of agents targeting key molecules in pathogenic pathways. A clinical trial that is currently being conducted by our group testing ustekinumab (anti-IL-23p40) (clinicaltrials.gov, NCT01806662) in AD patients may help elucidate the effects of IL-17A inhibition on Th2 cytokine induction. By inhibiting Th17 T-cell activation (and thus significant IL-17 production) with this biologic, we will be able to evaluate the posttreatment effects of such a blockade on all the major inflammatory axes, including Th2 T cells and their associated markers. In doing so, our study may bridge the murine work by Nakajima et al. (2014) to humans, potentially providing insights into whether IL-17 inhibition truly reduces Th2 activity. Conversely, dupilumab (clinicaltrials.gov, NCT01859988), a mAb that inhibits IL-4Rα, dually blocking IL-4 and IL-13 signaling may shed light on the effects of Th2 inhibition on the IL-17 pathway genes in addition to the other major T-cell axes. Moving forward, a bedside-to-bench approach with pathway-targeted therapeutics will enable us to not only test the efficacies of these drugs but also potentially unveil additional novel targets in the major inflammatory pathways. The work by Nakajima et al. (2014) in this issue of the journal, however, presents a fascinating model for the initiation of Th2 inflammation in AD, providing a potential therapeutic target and an exciting clue into the early stages of the slowly unraveling AD pathogenesis model.