Portal de Periódicos da CAPES

A New Player on the Psoriasis Block: IL-17A- and IL-22-Producing Innate Lymphoid Cells

2014; Elsevier BV; Volume: 134; Issue: 9 Linguagem: Inglês

10.1038/jid.2014.216

1523-1747

Nicole L. Ward, Dale T. Umetsu,

Psoriasis: Treatment and Pathogenesis

Innate lymphoid cells (ILCs) are a recently discovered family of innate immune cells belonging to the lymphoid lineage, yet lacking antigen-specific receptors. ILCs were first identified in the intestinal tract, where they contribute to epithelial barrier integrity and host responses to commensal microbes. Teunissen et al. (in the current issue) and Villanova et al. (2014) now suggest an important role for type 3 ILCs (ILC3s) in the skin, particularly in psoriasis. Both groups found an increased frequency of IL-22- and/or IL-17A-producing ILCs in psoriatic skin and blood. These cells are activated in response to IL-1β and IL-23, correlate with disease severity, and are decreased following antitumor necrosis factor-α (anti-TNFα) treatment. The presence of a novel ILC population in psoriatic skin, one that responds to biologic therapeutics, suggests that dysregulation of ILCs is a contributing factor to psoriasis pathogenesis. Innate lymphoid cells (ILCs) are a recently discovered family of innate immune cells belonging to the lymphoid lineage, yet lacking antigen-specific receptors. ILCs were first identified in the intestinal tract, where they contribute to epithelial barrier integrity and host responses to commensal microbes. Teunissen et al. (in the current issue) and Villanova et al. (2014) now suggest an important role for type 3 ILCs (ILC3s) in the skin, particularly in psoriasis. Both groups found an increased frequency of IL-22- and/or IL-17A-producing ILCs in psoriatic skin and blood. These cells are activated in response to IL-1β and IL-23, correlate with disease severity, and are decreased following antitumor necrosis factor-α (anti-TNFα) treatment. The presence of a novel ILC population in psoriatic skin, one that responds to biologic therapeutics, suggests that dysregulation of ILCs is a contributing factor to psoriasis pathogenesis. Innate lymphoid cells (ILCs) represent a family of multifunctional, lymphoid-lineage cells that lack B- and T-cell receptors and display innate immune effector functions. These cells often reside at mucosal interfaces where they rapidly produce cytokines in response to environmental challenges. At least three groups of ILCs have been identified, based upon unique transcription factor utilization, cytokine profiles, and effector functions. Groups 1 and 2 produce type 1 and 2 cytokines, respectively, whereas group 3 has a unique capacity to produce IL-17A and IL-22. Dysregulation of ILCs has been implicated in autoimmune and inflammatory diseases, thus broadening our understanding of how innate immune cells contribute to disease pathogenesis. However, less well understood until now is the potential role of ILCs in psoriasis. Two papers, both published in the Journal of Investigative Dermatology in 2014 (Teunissen et al., 2014Teunissen M. Munneke M. Bernink J. et al.Enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.146Abstract Full Text Full Text PDF Scopus (236) Google Scholar; Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, provide compelling evidence for a pathogenic role of ILCs in psoriasis. Teunissen et al., 2014Teunissen M. Munneke M. Bernink J. et al.Enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.146Abstract Full Text Full Text PDF Scopus (236) Google Scholar show the upregulation of group 3 ILCs (ILC3s) in nonlesional and lesional skin and in blood of psoriasis patients, and that these cells are novel cellular sources of IL-22 in the skin. Nestle and colleagues (Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar demonstrate a close association between disease improvement and the number of IL-17A- and IL-22-producing ILC3s in the skin and in circulation following antitumor necrosis factor-α (anti-TNFα) therapy, suggesting that ILC3s contribute to the pathogenesis of psoriasis. ILCs lack T-cell receptors and B-cell receptors, and therefore are antigen nonspecific; however, they respond rapidly to environmental challenges, such as tissue injury or infection, via cytokine secretion. Type 1 ILCs, or ILC1s, require the transcription factor T-bet, are induced in response to IL-12, produce type 1 cytokines such as IFNγ, and have been observed in the intestines of patients with inflammatory bowel disease. Type 2 ILCs, or ILC2s, require the transcription factor RORα and GATA3, respond to the innate cytokines IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), produce IL-5 and IL-13 but not IL-4, and have been found in the intestines in the context of helminth infection (Neill et al., 2010Neill D.R. Wong S.H. Bellosi A. et al.Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.Nature. 2010; 464: 1367-1370Crossref PubMed Scopus (1618) Google Scholar, in the lungs in the context of asthma (Chang et al., 2011Chang Y-J. Kim H. Albacker L. et al.Innate lymphoid cells mediate influenza-induced airway hyperreactivity independent of adaptive immunity.Nat Immunol. 2011; 12: 631-638Crossref PubMed Scopus (633) Google Scholar, and in the skin in the context of atopic dermatitis (Salimi et al., 2013Salimi M. Barlow J.L. Saunders S.P. et al.A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis.J Exp Med. 2013; 210: 2939-2950Crossref PubMed Scopus (668) Google Scholar. Type 3 ILCs, or ILC3s, require the transcription factor RORγt, respond to IL-23 and IL-1β, and produce IL-17A and/or IL-22. ILC3s producing IL-17A have been observed in the intestines of patients with Crohn’s disease (Coccia et al., 2012Coccia M. Harrison O.J. Schiering C. et al.IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells.J Exp Med. 2012; 209: 1595-1609Crossref PubMed Scopus (408) Google Scholar and in the lungs of patients with nonallergic asthma (Kim et al., 2014Kim H. Lee H. Chang Y-J. et al.IL-17 producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity.Nat Med. 2014; 20: 54-61Crossref PubMed Scopus (436) Google Scholar. A role for ILC3s in human skin has until now remained unexplained. In murine studies, psoriasiform skin inflammation was still observed in Aldara-treated Rag2−/− mice, despite the lack of lymphocytes and natural killer T cells (Hedrick et al., 2009Hedrick M.N. Lonsdorf A.S. Shirakawa A.K. et al.CCR6 is required for IL-23-induced psoriasis-like inflammation in mice.J Clin Invest. 2009; 119: 2317-2329Crossref PubMed Scopus (186) Google Scholar; Pantelyushin et al., 2012Pantelyushin S. Haak S. Ingold B. et al.Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice.J Clin Invest. 2012; 122: 2252-2256Crossref PubMed Scopus (400) Google Scholar. Sustained expression of IL-17A and IL-22 in the skin of these mice suggested an alternative innate cellular source for these psoriasis-critical cytokines. Indeed, Pantelyushin et al., 2012Pantelyushin S. Haak S. Ingold B. et al.Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice.J Clin Invest. 2012; 122: 2252-2256Crossref PubMed Scopus (400) Google Scholar demonstrated the presence of IL-22-producing ILC3s in Aldara-induced skin inflammation that mediated the inflammatory response to Aldara, because backcrossing the Rag2−/− mice with IL2rγc−/− mice, which lack ILCs, eliminated the response to Aldara. The work of Teunissen et al., 2014Teunissen M. Munneke M. Bernink J. et al.Enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.146Abstract Full Text Full Text PDF Scopus (236) Google Scholar in this issue, along with that recently published by Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, translates these findings into human skin disease and provides new insights into the role of ILC3s in psoriasis.These studies identify a novel ILC population in psoriatic skin that responds to biologic therapeutics, thus suggesting that dysregulation of ILCs is a contributing factor to psoriasis pathogenesis. In healthy skin and blood, ILC2 and ILC3s are present at low levels and express the cutaneous lymphocyte-associated antigen (CLA), thus having the capacity to localize in skin. Although few ILC3s are found in normal healthy skin, when grown ex vivo as cultured dermal explants, they express IL-22. Of particular translational importance were the findings by both Teunissen et al., 2014Teunissen M. Munneke M. Bernink J. et al.Enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.146Abstract Full Text Full Text PDF Scopus (236) Google Scholar and Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar showing increases in the ILC3 (and not the ILC1 or ILC2) population in involved- and uninvolved-psoriasis skin and in peripheral blood that produced IL-22 and possibly IL-17A, two cytokines known to be especially pathogenic in human psoriasis. Moreover, ILC3s cultured ex vivo responded to IL-1β and IL-23, cytokines known to be elevated in psoriasis, and this converted them to the activated natural cytotoxicity receptor positive (NCR+) form of ILC3 that produces IL-22. Although Teunissen et al., 2014Teunissen M. Munneke M. Bernink J. et al.Enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.146Abstract Full Text Full Text PDF Scopus (236) Google Scholar did not directly demonstrate ILC3-derived IL-17A in human psoriasis skin, Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar reported the ability of ILC3s in psoriasis skin and blood to produce both IL-17A and IL-22. These results may reflect methodological differences in how cells were isolated, the purity of the cell populations, and/or differences among the patients from whom the cells were taken. Interestingly, work performed in our laboratories using fresh psoriasis patient skin, both involved and uninvolved, has validated the increased presence (∼4-fold) of IL-22-producing ILC3s (S Yu, data not shown). However, we have not yet examined whether these cells produce IL-17A. All of these observations, taken together, suggest that ILC3s serve as innate counterparts to skin-resident memory T cells, are a significant source of pathogenic cytokines in psoriatic skin, and perhaps serve as a first line of defense in the skin, one that initiates the development of psoriasis. Another observation specifically relevant to psoriasis may be found in a recent report by one of the same groups (Hergen Spits and Jenny Mjosberg) who identified tonsil-resident ILC3s that also respond to IL-1β and IL-23 with the production of IL-22 and IL-17A (Bernink et al., 2013Bernink J.H. Peters C.P. Munneke M. et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues.Nat Immunol. 2013; 14: 221-229Crossref PubMed Scopus (726) Google Scholar. Considering recent evidence that psoriasis patients’ tonsils have a higher frequency of skin-homing lymphocytes (Sigurdardottir et al., 2013Sigurdardottir S.L. Thorleifsdottir R.H. Valdimarsson H. et al.The association of sore throat and psoriasis might be explained by histologically distinctive tonsils and increased expression of skin-homing molecules by tonsil T cells.Clin Exp Immunol. 2013; 174: 139-151Crossref PubMed Scopus (30) Google Scholar and that psoriasis patients often report onset or worsening of their skin disease after Streptococcal infection (Gudjonsson et al., 2003Gudjonsson J.E. Thorarinsson A.M. Sigurgeirsson B. et al.Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study.Br J Dermatol. 2003; 149: 530-534Crossref PubMed Scopus (168) Google Scholar, it will be interesting to determine whether tonsil-resident ILC3s in psoriasis patients upregulate CLA following Streptococcal infection. Such a relationship would support a role for ILC3s in psoriasis initiation and pathogenesis. Both Teunissen et al., 2014Teunissen M. Munneke M. Bernink J. et al.Enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.146Abstract Full Text Full Text PDF Scopus (236) Google Scholar and Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar demonstrated a correlation between ILC3 frequency and severity of psoriasis, as measured by using the psoriasis area severity index (PASI) scoring system, and Villanova et al., 2014Villanova F. Flutter B. Tosi I. et al.Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.J Invest Dermatol. 2014; 134: 984-991Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar have also demonstrated a 75% decrease in ILC3s following TNFα inhibition (using adalimumab) in one patient. These results extend the work of Powell et al., 2012Powell N. Walker A.W. Stolarczyk E. et al.The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells.Immunity. 2012; 37: 674-684Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, showing that IL-23 and TNFα can drive ILC3 differentiation, and of Zaba et al., 2009Zaba L.C. Suarez-Farinas M. Fuentes-Duculan J. et al.Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.J Allergy Clin Immunol. 2009; 124: 1022-1030Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, demonstrating that IL-17/TNFα signature transcriptome probe sets predict disease remission in patients treated with etanercept (soluble TNFα receptor). Thus, it is likely that ILC3s and their elaborated cytokines are suppressed following TNFα inhibition in patients who are responsive to TNFα inhibition. Similarly, it is likely that IL-12/23 inhibitors also target ILC3s, based upon the capacity of IL-23 to drive differentiation and secretion of IL-17A/IL-22 from ILC3s. While IL-17/IL-23 inhibitors are showing considerable efficacy in clinical trials for psoriasis, IL-22 inhibitors have thus far failed clinically for psoriasis. IL-22 appears to have a critical role in driving keratinocyte hyperproliferation, a major feature of psoriasis. However, targeting it directly may be insufficient. Targeting IL-23 or IL-17 (produced by T cells (αβ and γδ), neutrophils, and ILC3s) inhibits IL-17A directly, and it also likely targets T-cell– and ILC3-derived IL-22. It is possible that the combined targeting of both IL-17A and IL-22 leads to a better clinical resolution. Future work exploring relative cell-specific contributions to IL-17-mediated inflammatory responses may provide additional insights into key cellular players in psoriasis pathogenesis. We thank Dr Wendy Goodman for helpful feedback during the preparation of this commentary and Dr Sanhong Yu for her work examining ILC3s in psoriasis skin. NLW is supported by grants from the National Institutes of Health (P30AR39750, RO1AR063437, RO1AR062546, and R21AR063852) and the National Psoriasis Foundation. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the NIAMS or NIH.