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Thymic Stromal Lymphopoietin: To Cut a Long Story Short

Open AccessPublished:January 16, 2017DOI:https://doi.org/10.1016/j.jcmgh.2017.01.005
      Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.

      Keywords

      Abbreviations used in this paper:

      DC (dendritic cell), IFN (interferon), IL (interleukin), ILC (innate lymphoid cells), MAPK (mitogen-activated protein kinase), NF-κB (nuclear factor kappa B), TLR (toll-like receptor), TNF (tumor necrosis factor), Treg (regulatory T cells), TSLP (thymic stromal lymphopoietin), TSLPR (thymic stromal lymphopoietin protein receptor)
      TSLP is a cytokine involved in a plethora of physiologic and pathologic immune functions, including tolerance and allergy. The existence of two isoforms of the protein whose expression is driven by independent promoters can explain these contrasting activities.
      Cytokines (cyto, from Greek κύτταρο kyttaro “cell” + kines, from Greek κίνηση kinisi “movement”) are a broad category of small proteins whose release has an effect on the behavior of cells around them. They can act in an autocrine, paracrine, and/or endocrine fashion and are important in a number of biological processes including developmental processes during embryogenesis; however, they are particularly important in the regulation of immune responses. Cytokine types include chemokines, interferons (IFNs), lymphokines, interleukins (ILs), and tumor necrosis factors (TNFs). Because cytokines are important in intercellular and intracellular communications, they are produced by a broad range of cells such as fibroblasts, stromal, endothelial, or immune cells. They can be part of a physiological, homeostatic response or act as danger signals initiating inflammation in response to the detection of pathogens. Indeed, different isoforms of the same cytokine have been observed to mediate different effects according to the context, cellular source, and targets. These isoforms can be the result of alternative splicing, as is the case for IL15,
      • Onu A.
      • Pohl T.
      • Krause H.
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      Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms.
      • Nishimura H.
      • Yajima T.
      • Naiki Y.
      • et al.
      Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo.
      or result from the expression of separate genes for each isoform, as is the case for the IFN, IL28
      • Sheppard P.
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      • et al.
      IL-28, IL-29 and their class II cytokine receptor IL-28R.
      and IL17.
      • Li H.
      • Chen J.
      • Huang A.
      • et al.
      Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family.
      Here we will examine how thymic stromal lymphopoietin (TSLP) belongs to the category of cytokines with more than 1 isoform, and we will review recent data that shed light on a paradox: despite the necessity for TSLP in the homeostatic development of certain immune cell subsets, the same cytokine seems to exert potent proinflammatory actions, and its upregulation underlies numerous allergic reactions and allergy-related pathologies.

      Discovery and Initial Observations

      TSLP is an IL7-like cytokine initially discovered in the culture supernatant of a mouse thymic stromal cell line and shown to act as a growth factor for T and B cells.
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      • et al.
      A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells.
      The existence of a human orthologue with similar functions was shown some years later by Quentmeier et al,
      • Quentmeier H.
      • Drexler H.G.
      • Fleckenstein D.
      • et al.
      Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.
      who observed constitutive TSLP expression in heart, lung, prostate, and testis human tissues. In the same study the authors cloned human TSLP and characterized the signaling pathway triggered by the TSLP–thymic stromal lymphopoietin protein receptor (TSLPR) interaction. In both human and mouse, the receptor for TSLP is a heterodimer composed of a chain specific for TSLP and the IL7R α-chain
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      • Drexler H.G.
      • Fleckenstein D.
      • et al.
      Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.
      • Park L.S.
      • Martin U.
      • Garka K.
      • et al.
      Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor.
      • Pandey A.
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      • Baumann H.
      • et al.
      Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin.
      ; however, in contrast to IL7, TSLP signaling results in JAK3-independent STAT5 phosphorylation.
      • Quentmeier H.
      • Drexler H.G.
      • Fleckenstein D.
      • et al.
      Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.
      • Park L.S.
      • Martin U.
      • Garka K.
      • et al.
      Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor.
      Quentmeier et al observed that myeloid cells proliferate in response to human TSLP. These cell lines also upregulate granulocyte-macrophage colony-stimulating factor after conditioning; however, the authors demonstrate a direct effect of TSLP on the proliferation, independent from granulocyte-macrophage colony-stimulating factor and from the activity of mitogen-activated protein kinases (MAPKs).
      • Quentmeier H.
      • Drexler H.G.
      • Fleckenstein D.
      • et al.
      Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.
      TSLP also promotes the maturation of primary cells of myeloid origin, particularly CD11c+ dendritic cells (DCs), one of the subsets on which expression of IL7R and TSLPR is highest.
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      • Soumelis V.
      • Gorman D.M.
      • et al.
      Human thymic stromal lymphopoietin preferentially stimulates myeloid cells.
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      • Kanzler H.
      • et al.
      Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.
      TSLP is primarily expressed by epithelial cells and keratinocytes in the skin, gut, lungs,
      • Reche P.A.
      • Soumelis V.
      • Gorman D.M.
      • et al.
      Human thymic stromal lymphopoietin preferentially stimulates myeloid cells.
      and ocular tissue
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      • et al.
      Human corneal epithelium-derived thymic stromal lymphopoietin links the innate and adaptive immune responses via TLRs and Th2 cytokines.
      and seems to be involved in the regulation of inflammatory processes occurring at the barrier surfaces. It is also constitutively produced by the epithelial cells of Hassall corpuscles in the thymus, where it activates mature DCs and plasmacytoid dendritic cells to induce functionally different types of regulatory T (Treg) cells.
      • Watanabe N.
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      • Lee H.K.
      • et al.
      Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus.
      • Hanabuchi S.
      • Ito T.
      • Park W.R.
      • et al.
      Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus.
      However, recent studies revealed that other types of cells, such as mast cells,
      • Soumelis V.
      • Reche P.A.
      • Kanzler H.
      • et al.
      Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.
      • Okayama Y.
      • Okumura S.
      • Sagara H.
      • et al.
      FcepsilonRI-mediated thymic stromal lymphopoietin production by interleukin-4-primed human mast cells.
      cancer cells,
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      Thymic stromal lymphopoietin and cancer.
      basophils,
      • Sokol C.L.
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      • Farr A.G.
      • et al.
      A mechanism for the initiation of allergen-induced T helper type 2 responses.
      and DCs, produce TSLP.
      • Kashyap M.
      • Rochman Y.
      • Spolski R.
      • et al.
      Thymic stromal lymphopoietin is produced by dendritic cells.
      In particular, DCs can be robust producers of TSLP under certain conditions; on in vitro cultured DCs, activation of toll-like receptors (TLRs) by lipopolysaccharide and CpG oligodeoxynucleotides induces a significant upregulation of TSLP mRNA expression in a STAT6-dependent fashion. In vivo challenge with house dust mite, a well-known allergen for triggering asthmatic responses, induces TSLP production by both epithelial and dendritic cells in the lungs.
      • Kashyap M.
      • Rochman Y.
      • Spolski R.
      • et al.
      Thymic stromal lymphopoietin is produced by dendritic cells.
      A more recent report confirms TSLP production by human DCs after challenge with β-glucans found on fungi. The authors show that IL1β, but not TNF-α, is necessary for TSLP production, and that this follows activation of both nuclear factor kappa B (NF-κB) and the p38 MAPK.
      • Elder M.J.
      • Webster S.J.
      • Williams D.L.
      • et al.
      TSLP production by dendritic cells is modulated by IL-1beta and components of the endoplasmic reticulum stress response.

      Functions of Thymic Stromal Lymphopoietin in Barrier Surfaces and the Emergence of a Paradox

      Innate and Adaptive Type 2 Immune Responses in Barrier Surfaces

      As reports for epithelial cell–DC interactions and the consequent immunomodulatory effects became more numerous,
      • Rimoldi M.
      • Chieppa M.
      • Salucci V.
      • et al.
      Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells.
      • Uhlig H.H.
      • Powrie F.
      Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses.
      • Rumbo M.
      • Schiffrin E.J.
      Ontogeny of intestinal epithelium immune functions: developmental and environmental regulation.
      • Komine M.
      • Karakawa M.
      • Takekoshi T.
      • et al.
      Early inflammatory changes in the “perilesional skin” of psoriatic plaques: is there interaction between dendritic cells and keratinocytes?.
      the effect of TSLP on adaptive immune responses through its action on DCs was also under investigation.
      It was observed that TSLP-conditioned peripheral blood CD11c+ DCs skew adaptive immune responses to a pathogenic and pro-allergic Th2 type. CD8 T cells expanded by TSLP-conditioned DCs produce the hallmark Tc2 cytokines IL5 and IL13, whereas concomitant activation of the DCs with CD40L induces potent cytotoxicity and IFN-γ secretion without dampening IL5 or IL13 secretion.
      • Gilliet M.
      • Soumelis V.
      • Watanabe N.
      • et al.
      Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells.
      Of note, CD4 T cells co-cultured with similarly activated DCs also acquire a strong Th2 phenotype but only in the absence of IL12.
      • Soumelis V.
      • Reche P.A.
      • Kanzler H.
      • et al.
      Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.
      • Ito T.
      • Wang Y.H.
      • Duramad O.
      • et al.
      TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand.
      Danger signals produced by the epithelia and secreted toward underlying tissues alert many cell subsets to the presence of pathogens/allergens. Thus DCs are not the only population of innate immune cells that responds to TSLP. Type 2 innate lymphoid cells (ILC2) robustly upregulate the hallmark Th2 cytokines IL4, IL5, and IL13 in response to TSLP alone or in synergy with other cytokines.
      • Licona-Limon P.
      • Kim L.K.
      • Palm N.W.
      • et al.
      TH2, allergy and group 2 innate lymphoid cells.
      On the skin, TSLP acts on resident ILC2 to induce Th2 cytokine secretion by the latter and promote inflammation. This cell subset is more abundant in atopic dermatitis lesions from patients, and it is also critical for the development of inflammation in a mouse model of the disease.
      • Kim B.S.
      • Siracusa M.C.
      • Saenz S.A.
      • et al.
      TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
      In the lungs, it is the synergy between TSLP, IL33, and IL25 that promotes expansion of type 2 ILCs in response to allergens such as papain
      • Halim T.Y.
      • Krauss R.H.
      • Sun A.C.
      • et al.
      Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation.
      and chitin as well as migratory helminths.
      • Mohapatra A.
      • Van Dyken S.J.
      • Schneider C.
      • et al.
      Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis.
      Consistently, a marked upregulation of TSLP expression has been repeatedly observed in mouse models of atopic dermatitis, allergy, eosinophilic esophagitis, and asthma.
      • Yoo J.
      • Omori M.
      • Gyarmati D.
      • et al.
      Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin.
      • Zhou B.
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      • De Smedt T.
      • et al.
      Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice.
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      • Headley M.B.
      • Zhou B.
      • Shih W.X.
      • et al.
      TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses.
      Elevated TSLP expression has been observed in eosinophilic esophagitis patients, in whom a gain-of-function polymorphism is associated with increased basophil responses in these patients.
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      Atopic dermatitis, asthma, psoriasis, and allergic rhinitis patients also show higher TSLP expression in inflamed tissues,
      • Soumelis V.
      • Reche P.A.
      • Kanzler H.
      • et al.
      Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.
      • Ying S.
      • O'Connor B.
      • Ratoff J.
      • et al.
      Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity.
      • Mou Z.
      • Xia J.
      • Tan Y.
      • et al.
      Overexpression of thymic stromal lymphopoietin in allergic rhinitis.
      • Nagarkar D.R.
      • Poposki J.A.
      • Tan B.K.
      • et al.
      Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis.
      • Volpe E.
      • Pattarini L.
      • Martinez-Cingolani C.
      • et al.
      Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis.
      whereas expression of TSLPR is modulated in these diseases compared with the steady state.
      • Froidure A.
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      • Gras D.
      • et al.
      Myeloid dendritic cells are primed in allergic asthma for thymic stromal lymphopoietin-mediated induction of Th2 and Th9 responses.
      • Lin S.C.
      • Huang J.J.
      • Wang J.Y.
      • et al.
      Upregulated thymic stromal lymphopoietin receptor expression in children with asthma.
      In humans, the balance between TSLP secretion by the epithelia and TSLPR expression levels on target cells is pivotal.

      Regulatory Immune Responses in the Gastrointestinal Tract

      Despite the aforementioned proinflammatory activity of TSLP in barrier surfaces such as skin and lung,
      • Soumelis V.
      • Reche P.A.
      • Kanzler H.
      • et al.
      Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.
      • Ying S.
      • O'Connor B.
      • Ratoff J.
      • et al.
      Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity.
      the cytokine is also known to be pivotal for the maintenance of homeostasis and the development of natural Treg in the gastrointestinal tract.
      First, it appears that polarization of type 2 ILCs is independent of TSLP in the gut and is rather controlled by IL33
      • Chu D.K.
      • Llop-Guevara A.
      • Walker T.D.
      • et al.
      IL-33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization.
      and the abundance of vitamins such as retinoic acid and vitamin D.
      • Ruiter B.
      • Patil S.U.
      • Shreffler W.G.
      Vitamins A and D have antagonistic effects on expression of effector cytokines and gut-homing integrin in human innate lymphoid cells.
      More specifically, retinoic acid synergizes with IL2, IL25, and IL33 but not TSLP to upregulate secretion of IL5 and IL13 as well as the gut homing integrins α4 and β7 on human ILC2 in vitro. This upregulation is inhibited by the addition of vitamin D in the culture medium in a dose-dependent fashion.
      • Ruiter B.
      • Patil S.U.
      • Shreffler W.G.
      Vitamins A and D have antagonistic effects on expression of effector cytokines and gut-homing integrin in human innate lymphoid cells.
      Moreover, gut epithelial cell lines selectively upregulate TSLP on stimulation with bacteria in a strain-dependent fashion, and this upregulation synergizes with transforming growth factor-β to promote the differentiation of Treg cells through the induction of IL10 production by DCs.
      • Zeuthen L.H.
      • Fink L.N.
      • Frokiaer H.
      Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-beta.
      After the first observations for the intestinal epithelial cells’ pivotal contribution to the shaping of adaptive immune responses,
      • Rimoldi M.
      • Chieppa M.
      • Salucci V.
      • et al.
      Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells.
      • Zaph C.
      • Troy A.E.
      • Taylor B.C.
      • et al.
      Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis.
      • Xu W.
      • He B.
      • Chiu A.
      • et al.
      Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI.
      TSLP was identified as one of the key mediators produced by primary human intestinal epithelial cells for the conditioning of CD103+ DCs to a tolerogenic phenotype.
      • Iliev I.D.
      • Spadoni I.
      • Mileti E.
      • et al.
      Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.
      In the latter study, we showed that supernatant from primary healthy intestinal epithelial cells boosts the capacity of CD103+ DCs to induce Foxp3 expression in naive T cells. This regulatory interaction is not observed when intestinal epithelial cells from Crohn’s disease patients were used for DC conditioning, and this is mainly attributed to the complete absence of TSLP expression in Crohn’s disease intestinal epithelial cells, when in contrast, healthy intestinal epithelial cells produce copious amounts of the cytokine. However, we also showed that in the mouse, expression of TSLPR in DCs is dispensable for Treg induction,
      • Iliev I.D.
      • Mileti E.
      • Matteoli G.
      • et al.
      Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning.
      indicating either that TSLP is not involved in Treg development via DCs in the mouse or that signaling through the receptor is not required.
      In the intestine, DC-derived TSLP has also been shown to favor Treg over Th17 responses acting directly on T cells,
      • Spadoni I.
      • Iliev I.D.
      • Rossi G.
      • et al.
      Dendritic cells produce TSLP that limits the differentiation of Th17 cells, fosters Treg development, and protects against colitis.
      whereas delivery of TSLP by using recombinant lactic acid bacteria exerts a protective effect in the mouse model of dextran sodium sulfate–induced colitis.
      • Aubry C.
      • Michon C.
      • Chain F.
      • et al.
      Protective effect of TSLP delivered at the gut mucosa level by recombinant lactic acid bacteria in DSS-induced colitis mouse model.
      By using the same disease model, Reardon et al
      • Reardon C.
      • Lechmann M.
      • Brustle A.
      • et al.
      Thymic stromal lymphopoetin-induced expression of the endogenous inhibitory enzyme SLPI mediates recovery from colonic inflammation.
      observed impaired recovery and increased mortality of mice lacking TSLP, whereas ablation of the TSLP-TSLPR interaction in TSLPR knockout mice also leads to increased susceptibility to helminth infection, which in this case is attributed to the uncontrolled Th1/Th17 response due to the complete lack of Th2 responses.
      • Taylor B.C.
      • Zaph C.
      • Troy A.E.
      • et al.
      TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis.
      Mosconi et al
      • Mosconi I.
      • Geuking M.B.
      • Zaiss M.M.
      • et al.
      Intestinal bacteria induce TSLP to promote mutualistic T-cell responses.
      also showed that constitutive TSLP expression in the gut requires epithelial challenge by intestinal bacteria and has an important role in limiting the expansion of Th17 cells. The authors showed that in mice colonized with the benign altered Schadler flora, the TSLP-TSLPR interaction is key for the expansion of Helios-Foxp3+ Treg cells, and TSLPR–/– mice develop inappropriate Th17 responses in this model.

      Emergence of a Paradox

      Thus, we have so far seen that although expression of TSLP seems to be constitutive and homeostatic in certain tissues, an aberrant expression can lead to the development of a number of pathologies. Complete absence of the cytokine also seems to be an intriguing characteristic feature of autoimmune diseases such as Crohn’s disease, where inflammation is mostly Th1 and Th17 related.
      • Brand S.
      Crohn's disease: Th1, Th17 or both? the change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease.
      The data available create a paradox in which the action of TSLP might be tissue specific (proinflammatory in skin and lungs but homeostatic in gut and thymus) or context specific; the cytokine could contribute to the maintenance of homeostasis by actively promoting Treg cell development or indirectly by dampening exacerbated Th1 responses by skewing T-cell phenotype to Th2.
      • Taylor B.C.
      • Zaph C.
      • Troy A.E.
      • et al.
      TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis.
      • Sato-Deguchi E.
      • Imafuku S.
      • Chou B.
      • et al.
      Topical vitamin D(3) analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions.
      Of note, the capacity of TSLP to inhibit IL12 secretion by human monocyte-derived DCs only occurs within a short “window” of concentrations, and it is absent in the high concentrations used in previous studies,
      • Rimoldi M.
      • Chieppa M.
      • Salucci V.
      • et al.
      Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells.
      • Soumelis V.
      • Liu Y.J.
      Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation.
      indicating the need for strict regulation of the cytokine expression for its homeostatic effects to be properly manifested.
      The paradox of a dual role for TSLP is also evident in other pathologies such as cancer malignancies, with a number of studies showing opposite effects of TSLP overexpression on tumor growth and cell proliferation. Two independent studies report that TSLP expression by stromal or cancer cells contributes to tumor growth promoting a Th2-like environment in the tumor.
      • De Monte L.
      • Reni M.
      • Tassi E.
      • et al.
      Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer.
      • Pedroza-Gonzalez A.
      • Xu K.
      • Wu T.C.
      • et al.
      Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation.
      A role for TSLP in tumor growth through the regulation of the immune system is also supported by other studies in mouse models where an inhibition of tumor growth in TSLP-deficient hosts is observed.
      • Olkhanud P.B.
      • Rochman Y.
      • Bodogai M.
      • et al.
      Thymic stromal lymphopoietin is a key mediator of breast cancer progression.
      • Erdmann R.B.
      • Gartner J.G.
      • Leonard W.J.
      • et al.
      Lack of functional TSLP receptors mitigates Th2 polarization and the establishment and growth of 4T1 primary breast tumours but has different effects on tumour quantities in the lung and brain.
      However, more recently, different works in both the mouse and human system suggest a tumor-suppressing effect for TSLP for early pancreatic tumor,
      • Demehri S.
      • Cunningham T.J.
      • Manivasagam S.
      • et al.
      Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis.
      skin cancer,
      • Demehri S.
      • Turkoz A.
      • Manivasagam S.
      • et al.
      Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin.
      • Di Piazza M.
      • Nowell C.S.
      • Koch U.
      • et al.
      Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting.
      and colon cancer.
      • Yue W.
      • Lin Y.
      • Yang X.
      • et al.
      Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells.
      Di Piazza et al
      • Di Piazza M.
      • Nowell C.S.
      • Koch U.
      • et al.
      Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting.
      and Demehri et al
      • Demehri S.
      • Cunningham T.J.
      • Manivasagam S.
      • et al.
      Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis.
      • Demehri S.
      • Turkoz A.
      • Manivasagam S.
      • et al.
      Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin.
      demonstrate that the ablation of the TSLP-TSLPR signaling accelerates tumor growth in different murine models of skin carcinogenesis. TSLP levels are also negatively correlated with the clinical score of colon cancer patients. In this work, Yue et al
      • Yue W.
      • Lin Y.
      • Yang X.
      • et al.
      Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells.
      show that TSLP promotes the apoptosis of human colon cancer cells in a TSLPR-dependent manner.

      Human Thymic Stromal Lymphopoietin: Two Isoforms to Explain the Paradox?

      Two Isoforms Differentially Regulated

      In 2009, Harada et al
      • Harada M.
      • Hirota T.
      • Jodo A.I.
      • et al.
      Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells.
      described the existence of 2 different variants for TSLP in human bronchial epithelial cells. In this study, the authors observed that polyinosinic-polycytidylic acid, a TLR-3 ligand that was previously shown to upregulate TSLP,
      • Allakhverdi Z.
      • Comeau M.R.
      • Jessup H.K.
      • et al.
      Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells.
      • Kato A.
      • Favoreto Jr., S.
      • Avila P.C.
      • et al.
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      actually only induces the significant upregulation of a long isoform of TSLP. A shorter isoform, composed of the last 63 amino acids of the longer one, is constitutively expressed in normal human lung fibroblasts, and its expression is not changed after challenge with lipopolysaccharide or polyinosinic-polycytidylic acid. It was initially thought that these 2 isoforms were the result of alternative splicing,
      • Harada M.
      • Hirota T.
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      • et al.
      Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells.
      but, 1 year later, the same group reported the existence of 2 distinct 5′-untranslated regions resulting in 2 different open reading frames for TSLP in the human genome.
      • Harada M.
      • Hirota T.
      • Jodo A.I.
      • et al.
      Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.
      Of note, none of the studies published earlier had used tools to differentially analyze the expression or function of the 2 isoforms, and hence the observed effects of TSLP could have been attributed to either 1 of the 2 isoforms. Harada et al also examined 2 polymorphisms upstream the long isoform untranslated region that apparently increase transcription factor binding and, consequently, long TSLP expression. These 2 polymorphisms correlate positively with asthma susceptibility, whereas this is not true for the rs2289278 polymorphism, which is found in the second intron of the long form.
      • Harada M.
      • Hirota T.
      • Jodo A.I.
      • et al.
      Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.
      After these studies on bronchial epithelial cells and because of the previously shown relevance of TSLP in the context of atopic skin diseases, Xie et al
      • Xie Y.
      • Takai T.
      • Chen X.
      • et al.
      Long TSLP transcript expression and release of TSLP induced by TLR ligands and cytokines in human keratinocytes.
      went on to study the expression and differential modulation of the 2 isoforms in human keratinocytes. The strategy they followed was to use primers specific for the long isoform and compare the observed long TSLP expression with the total TSLP expression. The group confirmed that ligands for TLRs 2, 3, 5, and 6 only significantly upregulate long TSLP, an effect reproduced in the presence of an atopic cytokine milieu (IL4, IL5, and TNF-α). On the contrary, vitamin D and its analogues upregulate total but not long TSLP transcription, despite previous references to a vitamin D responsive element in the mouse TSLP gene promoter.
      • Li M.
      • Hener P.
      • Zhang Z.
      • et al.
      Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
      Of note, the authors noticed that in steady state, total TSLP transcripts are 2- to 3-log more abundant than long TSLP transcripts, indicating that the main isoform expressed by human keratinocytes in steady state is the short one, although nothing was so far reported about the potential biologic activity of short TSLP.
      Consistently, Cultrone et al
      • Cultrone A.
      • de Wouters T.
      • Lakhdari O.
      • et al.
      The NF-kappaB binding site located in the proximal region of the TSLP promoter is critical for TSLP modulation in human intestinal epithelial cells.
      showed that challenge of polarized intestinal epithelial cell lines with TLR agonists significantly upregulates long TSLP in an NF-κB–dependent fashion. After in silico analysis, the authors identified several putative binding sites for NF-κB and AP-1 within a 4-kilobase long region of the TSLP promoter (Figure 1). Targeted mutation of the more conserved proximal NF-κB binding site results in an abrogation of the IL1-dependent TSLP upregulation as observed in luciferase reporter assays. At the same time, another study confirmed the long isoform specific upregulation after challenge of primary human lung fibroblasts with TNF-α.
      • Datta A.
      • Alexander R.
      • Sulikowski M.G.
      • et al.
      Evidence for a functional thymic stromal lymphopoietin signaling axis in fibrotic lung disease.
      In agreement with the data by Cultrone et al, the 80-fold upregulation of the long isoform transcript was c-Jun dependent, whereas expression levels of the short isoform did not vary after TNF-α challenge. Conflicting data between the human and mouse system also emerged regarding the capacity of vitamin D to induce TSLP expression and cause Th2-dependent pathologies. In the article cited previously, Li et al
      • Li M.
      • Hener P.
      • Zhang Z.
      • et al.
      Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
      showed that when high concentrations of vitamin D are applied topically on the skin of mice (in which an open reading frame for the short isoform of TSLP is absent), subsequent TSLP upregulation results in the development of an atopic dermatitis–like phenotype.
      • Li M.
      • Hener P.
      • Zhang Z.
      • et al.
      Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
      However, these results were not confirmed in the human system in a more recent study that used primary human keratinocytes and skin biopsies.
      • Landheer J.
      • Giovannone B.
      • Sadekova S.
      • et al.
      TSLP is differentially regulated by vitamin D3 and cytokines in human skin.
      Here the authors observe no TSLP production by healthy keratinocytes or healthy skin biopsies with or without challenge by the relevant vitamin D analogues, despite the efficient upregulation of other well-described vitamin D target genes in these biopsies. Upregulation of TSLP is only observed when vitamin D is used to treat psoriasis patients, but in that case the authors reported an amelioration of the phenotype, which they attributed to the concomitant downregulation of other proinflammatory mediators such as IL12/23p40, IL1α, IL1β, and TNF-α.
      • Sato-Deguchi E.
      • Imafuku S.
      • Chou B.
      • et al.
      Topical vitamin D(3) analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions.
      Whether this was a direct effect of vitamin D or upregulation of a non-specified TSLP isoform was necessary for the dampening of proinflammatory activity was not addressed.
      Figure thumbnail gr1
      Figure 1The human TSLP gene locus. Different transcription factors bind to different promoter regions, inducing expression of long or short TSLP, depending on the context, tissue, and stimulus. RXR, retinoic X receptor; VDR, vitamin D receptor.
      In an effort to elucidate the relevance of TSLP isoforms in steady state and disease, we examined the differential expression and biologic activity of the 2 isoforms in vitro and in vivo.
      • Fornasa G.
      • Tsilingiri K.
      • Caprioli F.
      • et al.
      Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin.
      After an in silico analysis of the human TSLP locus, we showed that the 2 isoforms are not the result of alternative splicing of the same transcript but are rather controlled by 2 different promoter regions. We examined the ENCODE track profiles showing active enhancers (H3K4me1 high, H3K4me3 low, and H3K27ac high) or promoters (H3K4me1 low, H3K4me3 high, and H3K27ac high) as well as the ENCODE DNaseI hypersensitive site clusters (indicating promoter accessibility to transcription factors) derived from ChIP-seq experiments of 125 different cell types. This analysis predicted a much higher transcription factor activity for the promoter region of the short isoform, whereas scarce, if any, activity in the long isoform promoter was observed. Consistently, we found that in healthy barrier surfaces such as gut and skin, short TSLP is the main transcript variant detected. We confirmed previous observations that vitamin D only upregulates the short isoform of the protein on primary epithelial cells. In agreement with these results, in silico analysis has identified 1 putative vitamin D receptor binding site in intron 3 of the TSLP gene just upstream of the short isoform open reading frame (Figure 1). We also reproduced previous observations for bacterial strain-specific effects on TSLP secretion by human intestinal epithelial cells. Highly immunogenic strains such as Salmonella typhimurium and adherent-invasive Escherichia coli (a gift from Dr Arlette Darfeuille-Michaud) upregulate the long isoform and downregulate the short isoform, whereas the opposite is true after challenge with a commensal E coli strain (Figure 2). This could mean that the dysbiosis observed in many barrier surface pathologies could impact the usually balanced, homeostatic expression of TSLP.
      Figure thumbnail gr2
      Figure 2Induction of TSLP expression by endothelial cells and DC conditioning. In microbe-inhabited barrier surfaces, commensal bacteria such as E coli and nutrients such as vitamin D enhance short TSLP expression. Pathogens such as S typhimurium and allergens such as house dust mite upregulate the long isoform.

      Short Thymic Stromal Lymphopoietin Function

      Despite clear evidence of a dichotomy for the 2 isoforms of TSLP in humans, the role of the short isoform was poorly understood. Bjerkan et al
      • Bjerkan L.
      • Schreurs O.
      • Engen S.A.
      • et al.
      The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide.
      examined the expression and biologic activity of short TSLP on barrier surfaces such as the oral mucosa and the skin. Because the sequence of the 63 amino acids that make up short TSLP is completely homologous to the C-terminus of the long form, short form–specific antibodies are not available. Hence, we have seen that up to that point the differential expression of the 2 isoforms had only been studied by quantitative polymerase chain reaction analyses, with primer pairs specifically targeting one or the other transcript variant. In this work, the authors reproduced previous findings at the mRNA level, and they also used a clever indirect strategy to confirm the results at the protein level; commercially available polyclonal antibodies against total TSLP were incubated with synthetic short form TSLP coupled to CNBr-activated Sepharose 4B beads to remove antibody reactivity against the short isoform. By using this strategy, they showed that expression of TSLP on healthy barrier surfaces is limited to the short isoform, whereas long TSLP is only upregulated in oral mucosal lesions after challenge with smokeless tobacco. Because recombinant long TSLP had previously been observed to exert antimicrobial activities
      • Sonesson A.
      • Kasetty G.
      • Olin A.I.
      • et al.
      Thymic stromal lymphopoietin exerts antimicrobial activities.
      and this effect had been pinpointed to the last 34 amino acids of the cytokine, the authors assessed the antimicrobial activity of synthetic short TSLP and found that the growth of all bacterial strains tested was potently inhibited.
      • Bjerkan L.
      • Schreurs O.
      • Engen S.A.
      • et al.
      The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide.
      Subsequently, our own studies deepened knowledge on the functional properties of the 2 isoforms, revealed immunomodulatory activity for short TSLP, and partly explained the apparently contradictory results that had been obtained in different model systems and disease conditions in the previous years.
      • Fornasa G.
      • Tsilingiri K.
      • Caprioli F.
      • et al.
      Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin.
      We first addressed the biologic activity of the short isoform in vitro by conditioning with short TSLP monocyte-derived DCs, which do not express TSLPR if not activated. We found that in presence of short TSLP, DCs respond more mildly to bacterial infection. Moreover, IFN-γ production in allogenic bidirectional mixed lymphocyte reactions from healthy donors is dampened after short TSLP conditioning and increased in the presence of the long isoform. We also showed that the anti-inflammatory effect of short TSLP on human monocyte-derived DCs is mediated via an as yet undescribed molecular mechanism involving p38 phosphorylation rather than STAT5 phosphorylation through which the long isoform signals.
      • Fornasa G.
      • Tsilingiri K.
      • Caprioli F.
      • et al.
      Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin.

      Thymic Stromal Lymphopoietin Isoform Expression in Pathologies

      The expression of both TSLP isoforms in pathologies with a well-documented long TSLP contribution changes dramatically compared with the steady state. Interestingly, the pattern of expression is pathology-dependent (Table 1). By using long form–specific antibodies produced in our laboratory, we confirmed the specific upregulation of long but not short TSLP in biopsies from atopic dermatitis and ulcerative colitis patients.
      • Fornasa G.
      • Tsilingiri K.
      • Caprioli F.
      • et al.
      Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin.
      Interestingly, we also observed a significant downregulation of the short TSLP transcript in untreated celiac disease patients, which is in line with our group’s previous observations for reduced total TSLP expression in another intestinal pathology, Crohn’s disease.
      • Iliev I.D.
      • Spadoni I.
      • Mileti E.
      • et al.
      Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.
      The scarce expression of short TSLP and its potential relevance in refractory celiac disease are confirmed by Biancheri et al,
      • Biancheri P.
      • Di Sabatino A.
      • Rescigno M.
      • et al.
      Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease.
      who argue that restoring said expression could be a valid therapeutic strategy.
      Table 1Differential Expression of TSLP Isoforms in Barrier Surface Diseases
      PathologyShort TSLPLong TSLP
      Asthma-↑↑
      Crohn’s disease↓↓-
      Ulcerative colitis-
      Celiac disease↓↓↓↓
      Atopic dermatitis↓↓
      Psoriasis-↑↑
      -, unchanged; ↑↑, upregulated; ↓↓, downregulated.
      Volpe et al
      • Volpe E.
      • Pattarini L.
      • Martinez-Cingolani C.
      • et al.
      Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis.
      also detected a potential implication for TSLP in the IL23/IL17 proinflammatory axis, because they found the cytokine is significantly upregulated in psoriatic lesions but not normal skin from patients. They showed that in vitro, TSLP is capable of inducing the production of copious amounts of IL23 by primary human blood DCs in synergy with CD40L and TNF-α. Although in this study the authors did not distinguish between the 2 isoforms, data produced in our laboratory indicate long but not short TSLP upregulation with high statistical significance for this pathology (Table 1 and unpublished data).
      It is now recognized that in pathologic conditions, TSLP expression can also be controlled by endogenous proteases important to regulate its activity. Bianchieri et al demonstrated that the protease furin, which was upregulated in biopsies from untreated celiac disease patients, could degrade the long isoform producing fragments of 10 and 4 kDa that show different activity on human peripheral blood mononuclear cells compared with the mature TSLP.
      • Nagarkar D.R.
      • Poposki J.A.
      • Tan B.K.
      • et al.
      Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis.
      Similarly, another group demonstrate, in 2 distinct publications, that TSLP is truncated in 2 fragments (aa29-124 and aa131-159) by furin-like and carboxypeptidase N proteases in inflamed tissue. These fragments showed enhanced pro-Th2 activity on mast cells and ILC2 compared with the full mature long TSLP.
      • Nagarkar D.R.
      • Poposki J.A.
      • Tan B.K.
      • et al.
      Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis.
      • Poposki J.A.
      • Klingler A.I.
      • Stevens W.W.
      • et al.
      Proprotein convertases generate a highly functional heterodimeric form of thymic stromal lymphopoietin in humans.
      We have seen how in recent years, the dual role of TSLP and the dichotomy of the 2 isoforms’ expression in homeostasis and disease have been dissected by us and others. Despite the existence of a plethora of mouse models to study inflammatory bowel disease,
      • Kiesler P.
      • Fuss I.J.
      • Strober W.
      Experimental models of inflammatory bowel diseases.
      as well as other diseases, in which TSLP has a proven contribution and because the short isoform is absent in the mouse, these models are not indicated for the elucidation of the 2 isoforms’ potential role in these pathologies. Thus, it would be of great interest to examine the differential expression of the 2 isoforms in tissues from patients with diseases such as airway inflammation due to allergy, asthma, or chronic obstructive pulmonary disease, eosinophilic esophagitis, allergic rhinitis, chronic rhinosinusitis, etc.
      Because of the physiological relevance of long TSLP expression in all these diseases, the cytokine has been repeatedly suggested as a valid target for immunotherapy with antibodies that would target TSLP and/or prevent its binding to TSLPR. However, because it is now conclusively shown that the short isoform of TSLP has important homeostatic functions, this should be taken into account when designing adequate therapeutic strategies. Monoclonal antibodies used to neutralize long TSLP should ideally not interact or hamper in any way the homeostatic effects of short TSLP, whereas exogenous administration of short TSLP could mediate important regulatory effects and dampen proinflammatory activity, leading to the amelioration of pathologies such as celiac disease, Crohn’s disease, and psoriasis.

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