title: NLRP3 and ASC differentially affect the lung transcriptome during pneumococcal pneumonia.
abstract: Streptococcus pneumoniae is the most frequently isolated causative pathogen of community-acquired pneumonia, a leading cause of mortality worldwide. Inflammasomes are multiprotein complexes that play crucial roles in the regulation of inflammation. Nod-like receptor family, pyrin domain containing (NLRP) 3 is a sensor that functions in a single inflammasome, whereas adaptor apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) is a common adaptor of several inflammasomes. We investigated the role of NLRP3 and ASC during S. pneumoniae pneumonia by comparing bacterial growth and spreading, and host innate immune responses in wild-type mice and mice deficient for either NLRP3 (Nlrp3(-/-)) or ASC (Asc(-/-)). Asc(-/-) mice had increased bacterial dissemination and lethality compared with Nlrp3(-/-) mice, although the cytokine response was impaired in both mouse strains. By detailed analysis of the early inflammatory response in the lung by whole-genome transcriptional profiling, we identified several mediators that were differentially expressed between Nlrp3(-/-) and Asc(-/-) mice. Of these, IL-17, granulocyte/macrophage colony-stimulating factor, and integrin-αM were significantly attenuated in Asc(-/-) relative to Nlrp3(-/-) mice, as well as a number of genes involved in the adaptive immune response. These differences may explain the increased susceptibility of Asc(-/ -) mice during S. pneumoniae infection, and suggest that either ASC-dependent NLRP3-independent inflammasomes or inflammasome-independent ASC functions may be involved.
authors.affiliation: 1 Center of Infection and Immunity, Amsterdam, The Netherlands; and.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: van Lieshout
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000254:growth & development* / Q000472:pathogenicity; D013997:Time Factors; D059467:Transcriptome
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse