IL‐1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL‐1α and IL‐1β are translated as proforms that require cleavage for full cytokine activity and release, while IL‐1α is reported to occur as an alternative plasma membrane‐associated form on many cell types. However, the existence of cell surface IL‐1α (csIL‐1α) is contested, how IL‐1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL‐1α after ligation of TLRs. Pro‐IL‐1α tethers to the plasma membrane in part through IL‐1R2 or via association with a glycosylphosphatidylinositol‐anchored protein, and can be cleaved, activated, and released by proteases. csIL‐1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN‐γ, independent of expression level. We also reveal how prior csIL‐1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent‐associated secretory phenotype via csIL‐1α, but rather via soluble IL‐1α. We believe these data are important for determining the local or systemic context in which IL‐1α can contribute to disease and/or physiological processes.
Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.
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