Abstract
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1β secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger-associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through an NLRP3-inflammasome. Here, we show that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3-inflammasome-dependent secretion of IL-1β from macrophages. This process was dependent upon serine/threonine protein phosphatases since the PP1/PP2A inhibitors okadaic acid and calyculin A inhibited Sph-induced IL-1β release. IL-1β release induced by other well-characterized NLRP3-inflammasome activators, such as ATP and uric acid crystals, in addition to NLRC4 and AIM2 inflammasome activators was also blocked by these inhibitors. Thus, we propose Sph as a new DAMP, and that a serine/threonine phosphatase (PP1/PP2A)-dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasome activation.
Highlights
Inflammation is a crucial host response required for the clearance of pathogens and for the repair of injured tissue
IL-1b is produced in the macrophage cell cytosol as a precursor in response to pathogen-associated molecular patterns (PAMPs) such as LPS acting via Toll-like receptor 4 (TLR4) [4]
The priming stimulus in vivo during sterile inflammatory responses is not clear it has been suggested that several danger-associated molecular patterns (DAMPs), endogenous molecules released by dead cells or that are modified during disease, can act via the same receptors as PAMPs [5]
Summary
Inflammation is a crucial host response required for the clearance of pathogens and for the repair of injured tissue. IL-1b is produced in the macrophage cell cytosol as a precursor in response to pathogen-associated molecular patterns (PAMPs) such as LPS acting via Toll-like receptor 4 (TLR4) [4]. This is generally referred to as a ‘priming step’ and is required prior to the subsequent cytokine release. The priming stimulus in vivo during sterile inflammatory responses is not clear it has been suggested that several danger-associated molecular patterns (DAMPs), endogenous molecules released by dead cells or that are modified during disease, can act via the same receptors as PAMPs [5].
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