NLRP3 and ASC Differentially Affect the Lung Transcriptome during Pneumococcal Pneumonia

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- timulating factor, and integrin alpha M 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.