Notch1/Hes1PTEN/AKT/IL17A feedback loop regulates Th17 cell differentiation in mouse psoriasislike skin inflammation.
Mol Med Rep
; 26(1)2022 Jul.
Article
em En
| MEDLINE
| ID: mdl-35582997
IL17A, the effector cytokine of T helper (Th) 17 cells, plays a crucial role in the pathogenesis of psoriasis. The Notch1 and PI3K/AKT signaling pathways are implicated in Th17 cell differentiation and IL17A production. The present study aimed to evaluate the regulatory effect of the Notch1/hairy and enhancer of split 1 (Hes1)PTEN/AKT/IL17A feedback loop on Th17 cell differentiation via the PI3K/AKT inhibitor LY294002 in a mouse model of psoriasis. Mice were randomly divided into 3 groups: a control group, a model group [5% imiquimod (IMQ)induced group] and an intervention group (5% IMQinduced plus LY294002treated group). Skin structural characteristics were recorded and evaluated by hematoxylin and eosin staining. The weights of the spleens and inguinal lymph nodes were measured. Th17 cell percentage, as well as the mRNA and protein expression levels of Notch1, Notch1 intracellular domain (NICD1), Hes1, PTEN, AKT, phosphorylated (p)AKT, mTOR complex 1 (mTORC1), pmTORC1, S6 kinase (S6K)1, S6K2 and IL17A were detected in skin samples of the three experimental groups. Additionally, splenic mononuclear cells from model mice were treated by 10 and 50 µM LY294002 to further evaluate its regulatory effect on Notch1/Hes1PTEN/AKT/IL17A feedback loop. Increased Th17 cell percentage, increased expression of Notch1, NICD1, Hes1, AKT, pAKT, mTORC1, pmTORC1, S6K1, S6K2 and IL17A, and decreased PTEN levels were observed in model mice alongside marked psoriasislike skin inflammation, splenomegaly and lymphadenopathy. LY294002 treatment significantly alleviated the severity of psoriasislike skin inflammation in the intervention mice, attenuated the degree of epidermal hyperplasia and dermal inflammatory cell infiltration, and mitigated splenomegaly and lymphadenopathy. In addition, LY294002 treatment reversed the increased Th17 cell percentage, as well as the increased expression of Notch1, NICD1, Hes1, AKT, pAKT, mTORC1, pmTORC1, S6K1, S6K2 and IL17A, and the decreased expression of PTEN. In vitro study from 5% IMQinduced mouse splenic mononuclear cells presented that high dose of LY294002 exerted more obviously regulatory effect on Notch1/Hes1PTEN/AKT/IL17A feedback loop. The current findings suggested that the Notch1/Hes1PTEN/AKT/IL17A feedback loop regulates Th17 cell differentiation within the disease environment of psoriasis. Blocking the Notch1/Hes1PTEN/AKT/IL17A feedback loop may thus be a potential therapeutic method for management of psoriatic inflammation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Psoríase
/
Dermatite
/
Linfadenopatia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2022
Tipo de documento:
Article
País de publicação:
Grécia