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GM-CSF suppresses antioxidant signaling and drives IL-1β secretion through NRF2 downregulation


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-1β 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-1β 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-1β, 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-1β is through suppression of anti-oxidant responses, which leads to ubiquitylation of IL-1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signalling and reveals a novel mechanism for GM-CSF to promote inflammation.

SUBMITTER: Ms. Sara Di Carlo 

PROVIDER: S-SCDT-EMBOR-2021-54226-T | biostudies-other |

REPOSITORIES: biostudies-other

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