Downregulation of the Na/K-ATPase Pump by Leptospiral Glycolipoprotein Activates the NLRP3 Inflammasome

Abstract

Leptospira interrogans is responsible for a zoonotic disease known to induce severe kidney dysfunction and inflammation. In this work, we demonstrate that L. interrogans induces NLRP3 inflammasome-dependent secretion of IL-1β through the alteration of potassium transport in bone marrow-derived macrophages. Lysosome destabilization also contributed to the IL-1β production upon stimulation with live, but not dead, bacteria. Using bone marrow-derived macrophages from various TLRs and nucleotide-binding oligomerization domain-deficient mice, we further determined that IL-1β production was dependent on TLR2 and TLR4, suggesting a participation of the leptospiral LPS to this process. Hypokaliemia in leptospirosis has been linked to the presence of glycolipoprotein, a cell wall component of L. interrogans that is known to inhibit the expression and functions of the Na/K-ATPase pump. We show in this study that glycolipoprotein activates the inflammasome and synergizes with leptospiral LPS to produce IL-1β, mimicking the effect of whole bacteria. These results were confirmed in vivo, as wild-type mice expressed more IL-1β in the kidney than TLR2/4-deficient mice 3 d postinfection with L. interrogans. Collectively, these findings provide the first characterization, to our knowledge, of bacteria-induced activation of the NLRP3 inflammasome through the downregulation of a specific host potassium transporter.

Resibufogenin and Cinobufagin Activate Central Neurons through an Ouabain-Like Action

“…In response to inflammatory stimuli, ultralow concentrations (10 -6 µM) of ouabain restored Na + /K + -ATPase [16]. Participation of Na + /K + -ATPase in immune responses has been reported [51]. All of these studies support the idea that nanomolar concentrations of bufadienolides have anti-inflammatory effects that contribute to the efficacy of Lu-Shen-Wen in treating tonsillitis and sore throat.…”

Oleic acid inhibits lung Na/K-ATPase in mice and induces injury with lipid body formation in leukocytes and eicosanoid production

“…It has already been described that OA-induced ALI increased plasma PGE 2 levels [33]. The crosstalk of intracellular pathways with lipid body formation could stem from OA signaling, including inflammasome activation by the low intracellular concentration of K + due to pump inhibition [34]. However, this activation could also involve the role of this enzyme in other signal transduction pathways [35].…”

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

“…The upstream mechanism leading to NLRP3 inflammasome activation by these diverse activators is unclear. Studies investigating signaling upstream of inflammasome formation proposes that intracellular events, such as induction of hypokalemia or reactive oxygen species (ROS) indirectly activate the inflammasome [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] .…”