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      Thymic stromal lymphopoietin is a key cytokine for the immunomodulation of atherogenesis with Freund's adjuvant


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          Adaptive immune responses regulate the development of atherosclerosis, with a detrimental effect of type 1 but a protective role of type 2 immune responses. Immunization of Apolipoprotein E‐deficient (ApoE −/−) mice with Freund's adjuvant inhibits the development of atherosclerosis. However, the underlying mechanisms are not fully understood. Thymic stromal lymphopoietin (TSLP) is an IL7‐like cytokine with essential impact on type 2 immune responses (Th2). Thymic stromal lymphopoietin is strongly expressed in epithelial cells of the skin, but also in various immune cells following appropriate stimulation. In this study, we investigated whether TSLP may be crucial for the anti‐atherogenic effect of Freund's adjuvant. Subcutaneous injection of complete Freund's adjuvant (CFA) rapidly led to the expression of TSLP and IL1 β at the site of injection. In male mice, CFA‐induced TSLP occurred in immigrated monocytes—and not epithelial cells—and was dependent on NLRP3 inflammasome activation and IL1 β‐signalling. In females, CFA‐induced TSLP was independent of IL1 β and upon ovariectomy. CFA/OVA led to a more pronounced imbalance of the T cell response in TSLPR −/− mice, with increased INF γ/IL4 ratio compared with wild‐type controls. To test whether TSLP contributes to the anti‐atherogenic effects of Freund's adjuvant, we treated ApoE −/− and ApoE −/−/TSLPR −/− mice with either CFA/IFA or PBS. ApoE −/− mice showed less atherogenesis upon CFA/IFA compared with PBS injections. ApoE −/−/TSLPR −/− mice had no attenuation of atherogenesis upon CFA/IFA treatment. Freund's adjuvant executes significant immune‐modulating effects via TSLP induction. TSLP‐TSLPR signalling is critical for CFA/IFA‐mediated attenuation of atherosclerosis.

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          TSLP expression: cellular sources, triggers, and regulatory mechanisms.

          Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine initially identified in the culture supernatant of a thymic stromal cell line. Highly expressed in the epidermis in skin lesions of atopic dermatitis patients, TSLP was subsequently found to be a critical factor linking responses at interfaces between the body and environment (skin, airway, gut, ocular tissues, and so on) to Th2 responses. Recent studies have revealed that various cell types other than epithelial cells and epidermal keratinocytes (such as mast cells, airway smooth muscle cells, fibroblasts, dendritic cells, trophoblasts, and cancer or cancer-associated cells) also express TSLP. Environmental factors such as Toll-like receptor ligands, a Nod2 ligand, viruses, microbes, allergen sources, helminths, diesel exhaust, cigarette smoke, and chemicals trigger TSLP production. Proinflammatory cytokines, Th2-related cytokines, and IgE also induce or enhance TSLP production, indicating cycles of amplification. Skin barrier injury, increased epidermal endogenous protease activity, and less epidermal Notch signaling, all of which have been reported in atopic dermatitis, and keratinocyte-specific loss of retinoid X receptors and treatment of skin with agonists for vitamin D receptor in mice induce TSLP production, Th2 response, or atopic dermatitis-like inflammation. The transcription factors NF-κB and AP-1, nuclear receptors, single nucleotide polymorphisms, microRNAs, and the peptidyl-proryl isomerase Pin1 regulate TSLP mRNA expression transcriptionally or posttranscriptionally. This review focuses on events upstream of TSLP production, which is critical in allergic diseases and important in other TSLP-related disorders i.e. production sites, cellular sources, environmental and endogenous triggers and regulatory factors, and regulatory mechanisms of gene expression.
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            A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development

            Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor α chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor γ chain, γc. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, γc/TSLPR double KO mice had a greater lymphoid defect than γc KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in γc KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into γc KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4+ single positive thymocytes and peripheral T cells in vitro. Additionally, CD4+ T cells from TSLPR KO mice expanded less efficiently than WT CD4+ T cells in irradiated hosts, and TSLP preferentially expanded CD4+ T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4+ T cells.
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              Thymic stromal lymphopoietin is produced by dendritic cells.

              Thymic stromal lymphopoietin (TSLP) is a type 1 cytokine that contributes to lymphopoiesis and the development of asthma and atopic dermatitis. TSLP acts on multiple lineages, including dendritic cells (DCs), T cells, NKT cells, eosinophils, and mast cells, mediating proliferation and survival and linking innate and adaptive immune responses. TSLP is produced by a range of cells, including epithelial cells, fibroblasts, stromal cells, and keratinocytes. DCs are important primary targets of TSLP, and we unexpectedly demonstrated that DCs also produce TSLP in response to TLR stimulation and that this is augmented by IL-4. Moreover, we demonstrated that when mice were challenged with house dust mite extract, lung CD11c(+) DCs expressed TSLP mRNA at an even higher level than did epithelial cells. These data suggested that DCs not only respond to TSLP but also are a source of TSLP during pathogen and/or allergen encounter.

                Author and article information

                J Cell Mol Med
                J. Cell. Mol. Med
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                13 April 2020
                May 2020
                : 24
                : 10 ( doiID: 10.1111/jcmm.v24.10 )
                : 5731-5739
                [ 1 ] Klinik für Kardiologie und Angiologie Westdeutsches Herz‐ und Gefäßzentrum Universitätsklinikum Essen Essen Germany
                [ 2 ] Paris Cardiovascular Research Center INSERM U970 Paris France
                [ 3 ] Medizinische Klinik und Poliklinik II Universitätsklinikum Bonn Bonn Germany
                [ 4 ] Division of Cardiovascular Medicine Addenbrooke's Hospital University of Cambridge Cambridge UK
                Author notes
                [*] [* ] Correspondence

                Martin Steinmetz, Klinik für Kardiologie und Angiologie, Westdeutsches Herz‐ und Gefäßzentrum, Universitätsklinikum Essen, Essen, Germany.

                Email: martin.steinmetz@ 123456uk-essen.de

                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 0, Pages: 9, Words: 5300
                Funded by: Deutsche Forschungsgemeinschaft , open-funder-registry 10.13039/501100001659;
                Award ID: STE2067/1‐1
                Funded by: BONFOR
                Original Article
                Original Articles
                Custom metadata
                May 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:11.05.2020


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