BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis.
Cell Mol Immunol
; 15(12): 1047-1056, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-29670278
ABSTRACT
Leukotriene B4 (LTB4) synthesis is enhanced in the colonic mucosa in patients with inflammatory bowel disease (IBD). BLT1, a high-affinity receptor for LTB4, exhibits no effect on the progression of dextran sodium sulfate (DSS)-induced colitis, which mostly relies on innate immunity. Here, we reported that BLT1 regulates trinitrobenzene sulfonic acid (TNBS)-induced colitis, which reflects CD4+ T-cell-dependent adaptive immune mechanisms of IBD. We found that BLT1 signaling enhanced the progression of colitis through controlling the production of proinflammatory cytokines by dendritic cells (DCs) and modulating the differentiation of Th1 and Th17. BLT1-/- mice displayed an alleviated severity of TNBS-induced colitis with reduced body weight loss and infiltrating cells in the lamina propria. BLT1 deficiency in DCs led to reduced production of proinflammatory cytokines, including IL-6, TNF-α, and IL-12, and these results were further confirmed via treatment with a BLT1 antagonist. The impaired cytokine production by BLT1-/- DCs subsequently led to reduced Th1 and Th17 differentiation both in vitro and in vivo. We further performed a conditional DC reconstitution experiment to assess whether BLT1 in DCs plays a major role in regulating the pathogenesis of TNBS-induced colitis, and the results indicate that BLT1 deficiency in DCs also significantly reduces disease severity. The mechanistic study demonstrated that BLT1-regulated proinflammatory cytokine production through the Gαi ßγ subunit-phospholipase Cß (PLCß)-PKC pathway. Notably, we found that treatment with the BLT1 antagonist also reduced the production of proinflammatory cytokines by human peripheral blood DCs. Our findings reveal the critical role of BLT1 in regulating adaptive immunity and TNBS-induced colitis, which further supports BLT1 as a potential drug target for adaptive immunity-mediated IBD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Dendríticas
/
Doenças Inflamatórias Intestinais
/
Receptores do Leucotrieno B4
/
Colite
/
Colo
/
Células Th1
/
Células Th17
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Mol Immunol
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China