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Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis
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SYSNO ASEP 0599431 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis Tvůrce(i) Kuchař, Milan (BTO-N) RID, ORCID
Sloupenská, K. (CZ)
Kafkova, L. R. (CZ)
Groza, Yaroslava (BTO-N) ORCID
Škarda, J. (CZ)
Kosztyu, P. (CZ)
Hlavničková, Marie (BTO-N)
Mierzwicka, Joanna Maria (BTO-N)
Osička, Radim (MBU-M) RID, ORCID
Petroková, Hana (BTO-N) RID, ORCID
Walimbwa, S. I. (CZ)
Bharadwaj, Shiv (BTO-N)
Černý, Jiří (BTO-N) RID, ORCID
Raška, M. (CZ)
Malý, Petr (BTO-N) RID, ORCIDCelkový počet autorů 15 Číslo článku 469 Zdroj.dok. Cell communication and signaling : CCS - ISSN 1478-811X
Roč. 22, č. 1 (2024)Poč.str. 20 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova albumin-binding domain ; intestinal inflammation ; soluble receptor ; interleukin-22 ; cells ; innate ; cytokine ; immunity Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Cell biology CEP GF21-16423K GA ČR - Grantová agentura ČR Způsob publikování Open access Institucionální podpora BTO-N - RVO:86652036 ; MBU-M - RVO:61388971 UT WOS 001326714100003 EID SCOPUS 85205785575 DOI https://doi.org/10.1186/s12964-024-01846-w Anotace BackgroundHuman interleukin-22 (IL-22) is known as a dual function cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis.MethodsWe used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis.ResultsWe demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNF alpha/IFN gamma-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1 beta, IL-6, IL-10, and IL-17A.ConclusionsWe developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development. Pracoviště Biotechnologický ústav Kontakt Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Rok sběru 2025 Elektronická adresa https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01846-w
Počet záznamů: 1