Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F24%3A00599431" target="_blank" >RIV/61388971:_____/24:00599431 - isvavai.cz</a>

Alternative codes found

RIV/86652036:_____/24:00599431 RIV/61989592:15110/24:73627281 RIV/61988987:17110/24:A2503AK4 RIV/00843989:_____/24:E0111103

Result on the web

<a href="https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01846-w" target="_blank" >https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01846-w</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s12964-024-01846-w" target="_blank" >10.1186/s12964-024-01846-w</a>

Result language

angličtina

Original language name

Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell communication and signaling : CCS

ISSN

1478-811X

e-ISSN

1478-811X

Volume of the periodical

22

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

20

Pages from-to

469

UT code for WoS article

001326714100003

EID of the result in the Scopus database

2-s2.0-85205785575