Receptor-interacting protein 2 controls pulmonary host defense to Escherichia coli infection via the regulation of interleukin-17A

T Balamayooran, S Batra, G Balamayooran… - Infection and …, 2011 - Am Soc Microbiol
T Balamayooran, S Batra, G Balamayooran, S Cai, KS Kobayashi, RA Flavell, S Jeyaseelan
Infection and immunity, 2011Am Soc Microbiol
Recognition of microbial patterns by host receptors is the first step in a multistep sequence
leading to neutrophil-dependent host resistance. Although the role of membrane-bound
sensors in bacterial recognition has been examined in detail, the importance of cytosolic
sensors in the lungs is largely unexplored. In this context, there is a major lack of
understanding related to the downstream signaling mediators, such as cells and/or
molecules, during acute extracellular Gram-negative bacterial pneumonia. In order to …
Abstract
Recognition of microbial patterns by host receptors is the first step in a multistep sequence leading to neutrophil-dependent host resistance. Although the role of membrane-bound sensors in bacterial recognition has been examined in detail, the importance of cytosolic sensors in the lungs is largely unexplored. In this context, there is a major lack of understanding related to the downstream signaling mediators, such as cells and/or molecules, during acute extracellular Gram-negative bacterial pneumonia. In order to determine the role of NOD-like receptors (NLRs), we used an experimental Escherichia coli infection model using mice deficient in the gene coding for the NLR adaptor, receptor-interacting protein 2 (RIP2). RIP2−/− mice with E. coli infection displayed higher bacterial burden and reduced neutrophil recruitment and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP-2), and CXCL5/LIX expression, along with attenuated histopathological changes in the lungs. Decreased IL-17A levels were observed, along with lower numbers of IL-17A-producing T cells, in RIP2−/− mice after infection. RIP2−/− mice also show reduced IL-6 and IL-23 levels in the lungs, along with decreased activation of STAT3 after infection. Furthermore, activation of NF-κB and mitogen-activated protein kinases (MAPKs) and expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the lungs of infected RIP2−/− mice were attenuated following infection. Although neutrophil mobilization to the blood was impaired in RIP2−/− mice following infection, the expression of CD62P, CD11a/18, CD11b, and CXCR2 on blood and lung neutrophils was not altered between infected wild-type (WT) and RIP2−/− mice. Thus, RIP2 contributes to neutrophil-dependent host defense against an extracellular Gram-negative pathogen via (i) IL-17A regulation and (ii) neutrophil mobilization to the blood.
American Society for Microbiology