title: Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals.
abstract: Inflammation is the host response to microbial infection or sterile injury that aims to eliminate the insult, repair the tissue and restore homeostasis. Macrophages and the NLRP3 inflammasome are key sentinels for both types of insult. Although it is well established that the NLRP3 inflammasome is activated by microbial products and molecules released during sterile injury, it is unclear whether the responses elicited by these different types of signals are distinct. In this study, we used lipopolysaccharide and tumor necrosis factor as prototypical microbial and sterile signal 1 stimuli, respectively, to prime the NLRP3 inflammasome. We then used the bacterial toxin nigericin and a common product released from necrotic cells, ATP, as prototypical microbial and sterile signal 2 stimuli, respectively, to trigger the assembly of the NLRP3 inflammasome complex in mouse and human macrophages. We found that NLRP3 inflammasome responses were weakest when both signal 1 and signal 2 were sterile, but responses were faster and stronger when at least one of the two signals was microbial. Ultimately, the most rapid and potent responses were elicited when both signals were microbial. Together, these data suggest that microbial versus sterile signals are distinct, both kinetically and in magnitude, in their ability to generate inflammasome-dependent responses. This hierarchy of NLRP3 responses to sterile versus microbial stimuli likely reflects the urgent need for the immune system to respond rapidly to the presence of infection to halt pathogen dissemination.
authors.affiliation: Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, St Lucia, Queensland 4072, Australia.
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.affiliation: Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, St Lucia, Queensland 4072, Australia.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Coll
authors.affiliation: Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, St Lucia, Queensland 4072, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
mesh_terms: D000818:Animals; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014409:Tumor Necrosis Factor-alpha