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: Miriam H van Lieshout, Brendon P Scicluna, Sandrine Florquin, Tom van der Poll
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 50 Issue 4 Pg. 699-712 (Apr 2014) ISSN: 1535-4989 [Electronic] United States
• PMID: 24164497 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytokines
• Cytoskeletal Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Pycard protein, mouse

Topics

• Adaptive Immunity
• Animals
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins (genetics, metabolism)
• Cytokines (metabolism)
• Cytoskeletal Proteins (deficiency, genetics, metabolism)
• Disease Models, Animal
• Gene Expression Profiling
• Gene Expression Regulation
• Host-Pathogen Interactions
• Immunity, Innate
• Inflammasomes (immunology, metabolism)
• Lung (immunology, metabolism, microbiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Pneumonia, Pneumococcal (genetics, immunology, metabolism, microbiology)
• Streptococcus pneumoniae (growth & development, pathogenicity)
• Time Factors
• Transcriptome