Abstract
Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation.
Highlights
Macrophages are dynamic and versatile players of sterile and smoldering inflammation, due to the fact that they can mount, control, as well terminate inflammation [1,2]
In order to understand and assign a pharmacological relevance to S1P metabolic enzymes, we deciphered the role of S1P, upstream of S1PRs, in NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation and inflammation with the assumption that sphingosine kinases (SPHKs) might play an important role in this process
This supports the idea that SPHK1 may cooperate with TLR4 signaling in inflammatory responses independent of S1PR signaling and S1P production
Summary
Macrophages are dynamic and versatile players of sterile and smoldering inflammation, due to the fact that they can mount, control, as well terminate inflammation [1,2]. In an inflammatory setting, including cancer, macrophages can be primed and activated by a variety of damage-associated molecular patterns (DAMPs), including toll-like receptor (TLR) agonists such as HMGB1 or BD-2. These agonists are produced by injured or damaged cells, which provokes the secretion of interleukin-1 beta (IL-1β) and IL-18, amongst others. We recently demonstrated that in tumor-associated macrophages NLRP3 inflammasome activation and subsequent IL-1β release is downstream of sphingosine-1-phosphate receptor 1 (S1PR1) signaling [12]. If the inflammasome is regulated at the level of S1P kinases is unknown
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