Bacterial RNA mediates activation of caspase-1 and IL-1β release independently of TLRs 3, 7, 9 and TRIF but is dependent on UNC93B.
Recognition of foreign nucleic acids is important for the induction of an innate immune response against invading pathogens. Although the pathways involved in sensing bacterial DNA and viral RNA are now well established, only limited knowledge is available on mechanisms underlying recognition of bacterial RNA. It has been reported that intracellular delivery of Escherichia coli RNA activates the Nlrp3 inflammasome, but whether this is a general property of bacterial RNA remains unclear as are the pathways involved in pro-IL-1β induction and caspase-1 activation by bacterial RNA. In this study, we report that bacterial RNA from both Gram-positive and Gram-negative bacteria induces activation of caspase-1 and secretion of IL-1β by murine dendritic cells and bone-marrow derived macrophages. Stimulation was independent of the presence of 5'-triphosphate termini and occurred with whole RNA preparations from bacteria but not from eukaryotes. Induction of pro-IL-1β as well as the priming for caspase-1 activation by bacterial RNA was dependent on UNC93B, an endoplasmic reticulum protein essential for delivery of TLRs to the endosome, whereas the established nucleic acid sensing endosomal TLRs 3, 7, and 9 were dispensable. Additionally, caspase-1 activation and IL-1β production by transfected bacterial RNA were absent in MyD88-deficient cells but independent of TRIF. Thus, our data indicate the presence of a yet unidentified intracellular nucleic acid receptor involved in bacterial RNA-induced inflammasome activation and release of IL-1β.
Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, 69120 Heidelberg, Germany. tatjana.eigenbrod@med.uni-heidelberg.de
Tatjana
T
Eigenbrod
Luigi
L
Franchi
Raul
R
Muñoz-Planillo
Carsten J
CJ
Kirschning
Marina A
MA
Freudenberg
Gabriel
G
Núñez
Alexander
A
Dalpke
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D012329:RNA, Bacterial / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000502:physiology*; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D020170:Caspase 1; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D012329:RNA, Bacterial; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; C512254:UNC93B1 protein, mouse