HuR-Targeted Inhibition Impairs Th2 Proinflammatory Responses in Asthmatic CD4+ T Cells.
J Immunol
; 208(1): 38-48, 2022 01 01.
Article
en En
| MEDLINE
| ID: mdl-34862257
ABSTRACT
RNA-binding protein HuR (ELAVL1) is a master regulator of gene expression in human pathophysiology. Its dysregulation plays an important role in many diseases. We hypothesized that HuR plays an important role in Th2 inflammation in asthma in both mouse and human. To address this, we used a model of airway inflammation in a T cell-specific knockout mouse model, distal lck-Cre HuRfl/fl, as well as small molecule inhibitors in human peripheral blood-derived CD4+ T cells. Peripheral CD4+ T cells were isolated from 26 healthy control subjects and 45 asthmatics (36 type 2 high and 9 non-type 2 high, determined by blood eosinophil levels and fraction of exhaled NO). Our mouse data showed conditional ablation of HuR in T cell-abrogated Th2 differentiation, cytokine production, and lung inflammation. Studies using human T cells showed that HuR protein levels in CD4+ T cells were significantly higher in asthmatics compared with healthy control subjects. The expression and secretion of Th2 cytokines were significantly higher in asthmatics compared with control subjects. AMP-activated protein kinase activator treatment reduced the expression of several cytokines in both type 2 high and non-type 2 high asthma groups. However, the effects of CMLD-2 (a HuR-specific inhibitor) were more specific to endotype-defining cytokines in type 2 high asthmatics. Taken together, these data suggest that HuR plays a permissive role in both allergen and non-allergen-driven airway inflammation by regulating key genes, and that interfering with its function may be a novel method of asthma treatment.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Asma
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Células Th2
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Proteína 1 Similar a ELAV
Límite:
Adolescent
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Adult
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Aged
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Aged80
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Animals
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Immunol
Año:
2022
Tipo del documento:
Article