Age-Associated Inflammation and Toll-Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia

Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 09/2009; 200(4):546-54. DOI: 10.1086/600870
Source: PubMed


Aging is associated with increased inflammation and risk of community-acquired pneumonia. Streptococcus pneumoniae co-opts the nuclear factor kappa B (NFkB)-regulated proteins polymeric immunoglobulin receptor (pIgR) and platelet-activating factor receptor (PAFr) to attach and invade cells. We sought to determine whether aging and chronic inflammation were associated with increased pIgR and PAFr levels in the lungs and increased susceptibility to S. pneumoniae infection.
Lung protein and messenger RNA levels were quantitated using Western blot and quantitative polymerase chain reaction. NFkB activation was measured by electrophoretic mobility shift assay. Cytokine levels were measured by cytometric bead analysis. To model chronic inflammation, mice were implanted with osmotic pumps that delivered tumor necrosis factor-alpha.
Aged mice and those infused with tumor necrosis factor-alpha had increased levels of pIgR and PAFr in their lungs and were more susceptible to S. pneumoniae infection. During pneumonia, aged mice had reduced levels of pIgR and PAFr and less NFkB activation, despite greater bacterial burden. We determined that aged mice had decreased amounts of lung Toll-like receptors 1, 2, and 4 and reduced capacity to respond to S. pneumoniae with proinflammatory cytokine production.
Aged mice and, potentially, elderly humans are more susceptible to pneumonia because of a priming effect of chronic inflammation and Toll-like receptor dysfunction.

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    • "The increase in inflammation during aging has been linked to increased nuclear factor (NF) κB binding to DNA in many organs and tissues, as well as several types of blood borne cells [7]. NFκB is sensitive to oxidative stress and a variety of other stimuli and is responsible for the regulation of the transcription of a variety of gene targets, including pro-inflammatory cytokines such as interleukin (IL)-1, 6 and tumor necrosis factor (TNF)-α [8]. "
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    • "Both pIgR and PAFr are up-regulated by transcription factor NF-kB. Cells in acute and chronic states of inflammation have been found to express increased pIgR and PAFr and are bound by S. pneumoniae more often than resting cells.[30] "
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    • "Furthermore, results were confirmed in vitro with isolated alveolar macrophages stimulated with pneumococcal cell wall fraction and other known TLR agonists (unpublished data). It could be speculated that because IL-6 is required for production of acute phase proteins and to clear the infection by enhancing phagocytic killing, which probably does not occur due to delayed innate immune response and aged mice succumb to infection earlier than the healthy young mice [6]. Given the fact that pneumococcal adhesins PspA and CbpA interfere with the complement system and affect immune adherence and phagocytosis by macrophages [96, 97], it could be reasoned that, in addition to defective alveolar macrophage function, inhibition of complementation and phagocytosis may further affect clearance of the bacteria. "
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