GM-CSF suppresses antioxidant signaling and drives IL-1ß secretion through NRF2 downregulation.
EMBO Rep
; 23(8): e54226, 2022 08 03.
Article
en En
| MEDLINE
| ID: mdl-35695080
ABSTRACT
GM-CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM-CSF has been found to promote NLRP3-dependent IL-1ß secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM-CSF induces IL-1ß secretion through a ROS-dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL-1ß, promoting its cleavage through basal NRLP3 activity. GM-CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro-inflammatory effect of GM-CSF on IL-1ß is through suppression of antioxidant responses, which leads to ubiquitylation of IL-1ß and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM-CSF to promote inflammation.
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1
Banco de datos:
MEDLINE
Asunto principal:
Factor Estimulante de Colonias de Granulocitos y Macrófagos
/
Proteína con Dominio Pirina 3 de la Familia NLR
Idioma:
En
Revista:
EMBO Rep
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2022
Tipo del documento:
Article
País de afiliación:
Alemania