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Aryl hydrocarbon receptor regulates IL-22 receptor expression on thymic epithelial cell and accelerates thymus regeneration
- Source :
- npj Regenerative Medicine, Vol 8, Iss 1, Pp 1-10 (2023)
- Publication Year :
- 2023
- Publisher :
- Nature Portfolio, 2023.
-
Abstract
- Abstract Improving regeneration of damaged thymus is important for reconstituting T-cell immunity. Interleukin-22 (IL-22) was proved to improve thymus regeneration through recovering thymic epithelial cells (TECs). The IL-22 receptor IL-22RA1 is crucial for mediating IL-22 functions. Mechanism that regulates IL-22RA1 expression is unknown. Through using TECs-conditional knockout mice, we found aryl hydrocarbon receptor (AHR) is important for thymus regeneration, because Foxn1-cre-mediated AHR knockout (AhrKO) significantly blocks recovery of thymus cells. Giving mice the AHR inhibitor CH-223191 or the AHR agonist FICZ blocks or accelerates thymus regeneration, respectively. AhrKO-mediated blockade of thymus regeneration could not be rescued by giving exogenous IL-22. Mechanistically, AhrKO mice shows decreased IL-22RA1 expression. In the murine TECs cell line mTEC1 cells, targeting AHR shows an impact on IL-22RA1 mRNA levels. Using chromatin immunoprecipitation and luciferase reporter assays, we find AHR co-operates with STAT3, binds the promotor region of IL-22RA1 gene and transcriptionally increases IL-22RA1 expression in mTEC1 cells. Foxn1-cre-mediated IL-22RA1 knockout (Il22ra1KO) blocks thymus regeneration after irradiation. Furthermore, targeting AHR or IL-22RA1 has significant impacts on severity of murine chronic graft-versus-host disease (cGVHD), which is an autoimmune-like complication following allogeneic hematopoietic cell transplantation. Giving FICZ decreases cGVHD, whereas Il22ra1KO exacerbates cGVHD. The impacts on cGVHD are associated with thymus regeneration and T-cell immune reconstitution. In conclusion, we report an unrecognized function of TECs-expressed AHR in thymus regeneration and AHR transcriptionally regulates IL-22RA1 expression, which have implications for improving thymus regeneration and controlling cGVHD.
- Subjects :
- Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 20573995
- Volume :
- 8
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- npj Regenerative Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.95303311a454101b9e5174df90b9bab
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41536-023-00339-7