Potassium (K) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two-pore domain K channel (K) TWIK2 as the K efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6 macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti-inflammatory therapies.

Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb#10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean6SD baseline Hb was 8.361.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by $2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean6SEM maximal change in Hb from baseline (DHb max ), the primary endpoint, was 3.160.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, DHb max was similar and larger than in the no-iron group. Hb response (increase in Hb of $1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.

Highlights d Activated Gasdermin D forms mitochondrial pores in the endothelium d Mitochondrial pore formation releases mitochondrial DNA into the cytosol d Released mtDNA activates cGAS signaling and suppresses vascular regeneration d Deletion of cGAS in an experimental model of polymicrobial sepsis reduces tissue injury