{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:58:52Z","timestamp":1760144332268,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Interdisciplinary Center of Clinical Research","award":["Lud2\/013\/21","1009-B2"],"award-info":[{"award-number":["Lud2\/013\/21","1009-B2"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["Lud2\/013\/21","1009-B2"],"award-info":[{"award-number":["Lud2\/013\/21","1009-B2"]}]},{"name":"University of Muenster","award":["Lud2\/013\/21","1009-B2"],"award-info":[{"award-number":["Lud2\/013\/21","1009-B2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting psoriatic arthritis progression, even in the presence of the pro-inflammatory cytokine TNF\u03b1, by transforming dendritic cells (DCs) into tolerogenic cells and fostering regulatory Foxp3+ Treg cells. Here, we identified thymosins as the primary constituents of SSPs, but recombinant thymosin peptides were less efficient in inhibiting arthritis than SSPs. Since T\u03b24 is an ecto-ATPase-binding protein, we hypothesized that SSPs regulate exATP profiles. Real-time investigation of exATP levels in DCs revealed that tolerogenic stimulation led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in a less pronounced increase in exATP and less effective degradation. These contrasting exATP profiles were crucial in determining whether DCs entered an inflammatory or tolerogenic state, highlighting the significance of SSPs as natural regulators of peripheral immunological tolerance, with potential therapeutic benefits for autoimmune diseases. Finally, we demonstrated that the tolerogenic phenotype of SSPs is mainly influenced by adenosine receptors, and in vivo administration of SSPs inhibits psoriatic skin inflammation.<\/jats:p>","DOI":"10.3390\/biom14040469","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T09:37:31Z","timestamp":1712828251000},"page":"469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Small Spleen Peptides (SSPs) Shape Dendritic Cell Differentiation through Modulation of Extracellular ATP Synthesis Profile"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0307-6038","authenticated-orcid":false,"given":"Viktor","family":"Wixler","sequence":"first","affiliation":[{"name":"Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, Von-Esmarch-Str. 56, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Leite Dantas","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, Von-Esmarch-Str. 56, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1547-8766","authenticated-orcid":false,"given":"Georg","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology, University Children\u2019s Hospital Muenster, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-9010","authenticated-orcid":false,"given":"Yvonne","family":"Boergeling","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, Von-Esmarch-Str. 56, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-3052","authenticated-orcid":false,"given":"Stephan","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, Von-Esmarch-Str. 56, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.ymthe.2021.08.030","article-title":"Small spleen peptides prevent development of psoriatic arthritis via restoration of peripheral tolerance","volume":"30","author":"Wixler","year":"2022","journal-title":"Mol. 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