Downregulation of the Na/K-ATPase pump by leptospiral glycolipoprotein activates the NLRP3 inflammasome.
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.
Institut Pasteur, G5 Biologie et Génétique de la Paroi Bactérienne, Paris 75724, France.
Sonia
S
Lacroix-Lamandé
Martine Fanton
MF
d'Andon
Eric
E
Michel
Gwenn
G
Ratet
Dana J
DJ
Philpott
Stephen E
SE
Girardin
Ivo G
IG
Boneca
Alain
A
Vandewalle
Catherine
C
Werts
D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D007919:Leptospira / Q000276:immunology / Q000378:metabolism; D007922:Leptospirosis / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D001426:Bacterial Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C025431:extracellular slime proteins, bacterial; D000254:Sodium-Potassium-Exchanging ATPase