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

Hinojosa, Ernesto; Boyd, Angela R.; Orihuela, Carlos J.

doi:10.1086/600870

Cited by 135 publications

(138 citation statements)

References 47 publications

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“…TLR1 and -2 recognize cell wall-associated polysaccharide of pneumococcus (lipoteichoic acid) (31,32), and NOD2 recognizes peptidoglycan (22); both types of recognition upregulate inflammatory components, leading to macrophage influx and pathogen clearance. Furthermore, it has been reported in a mouse model of invasive pneumonia that protein levels of TLR1 and -2 are significantly decreased in aged compared to young adult mice following infection (7). We investigated the expression of these PRRs in the URTs of aged mice before and during colonization and found no statistical differences between age groups both before and during colonization in the epithelium.…”

Section: Figmentioning

confidence: 83%

“…Hinojosa et al (7) have recently shown an association of decreased protein levels of Toll-like receptor 1 (TLR1) and TLR2 in lung homogenates and increased levels of proinflammatory cytokines at baseline in elderly mice with higher mortality in a model of invasive pneumococcal pneumonia. These data suggest that there are innate defects in the lungs of elderly mice that likely contribute to increased risk and severity of pneumonia.…”

mentioning

confidence: 99%

“…Other groups have also sought to elucidate the mechanisms of immunosenescence of the innate compartment; however, most of these studies were performed in vitro (9-12) using primary cells known to change phenotype ex vivo (e.g., macrophages) (13) and/or used antigens such as lipopolysaccharide (LPS) that are relevant for Gram-negative bacteria but not for Gram-positive bacteria such as S. pneumoniae. Furthermore, in vivo infection models (7,14,15) and in vitro work using alveolar macrophages (14,15) are not informative regarding the prerequisite colonization state before pneumonia develops.…”

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confidence: 99%

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Impaired Innate Mucosal Immunity in Aged Mice Permits Prolonged Streptococcus pneumoniae Colonization

et al. 2013

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Streptococcus pneumoniae is a frequent asymptomatic colonizer of the nasopharyngeal niche and only occasionally progresses toward infection. The burden of pneumococcal disease is particularly high in the elderly, and the mechanisms behind this increased susceptibility are poorly understood. Here we used a mouse model of pneumococcal carriage to study immunosenescence in the upper respiratory tract (URT). Nasal mucosa-associated lymphoid tissue (NALT) showed increased expression of Toll-like receptor 1, interleukin-1␤, NLRp3 inflammasome, and CCL2 in naive elderly compared to young animals. This suggests an increased proinflammatory expression profile in the NALT of aged mice at baseline. Simultaneously, we observed a more tolerogenic profile in respiratory epithelia of naive elderly compared to young adult mice with upregulation of the NF-␤ pathway inhibitor peroxisome proliferator-activated receptor gamma (PPAR␥). After nasal instillation of pneumococci, pneumococcal colonization was prolonged in elderly mice compared to in young adults. The delay in clearance was associated with absent or delayed upregulation of a proinflammatory mediator(s) in the NALT, diminished influx of macrophages into the URT niche, and absent downregulation of PPAR␥ in respiratory epithelium, accompanied by diminished expression of cathelicidin (CRAMP) at the site of colonization. These findings suggest that unresponsiveness to pneumococcal challenge due to altered mucosal immune regulation is the key to increased susceptibility to disease in the elderly.

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Section: Figmentioning

confidence: 83%

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confidence: 99%

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confidence: 99%

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Impaired Innate Mucosal Immunity in Aged Mice Permits Prolonged Streptococcus pneumoniae Colonization

et al. 2013

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“…In the setting of pneumococcal challenge, chronic upregulation of PAFr promotes bacterial invasion and predisposes SCD individuals to invasive disease (7,9,27). Statins are potent inhibitors of systemic inflammation (16,26,29) and thus might serve as a prophylactic measure for SCD individuals, potentially reducing the incidence and severity of pneumococcal infection.…”

Section: Discussionmentioning

confidence: 99%

Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease

et al. 2010

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Sickle cell disease (SCD) is characterized by intravascular hemolysis and inflammation coupled to a 400-fold greater incidence of invasive pneumococcal infection resulting in fulminant, lethal pneumococcal sepsis. Mechanistically, invasive infection is facilitated by a proinflammatory state that enhances receptor-mediated endocytosis of pneumococci into epithelial and endothelial cells. As statins reduce chronic inflammation, in addition to their serum cholesterol-lowering effects, we hypothesized that statin therapy might improve the outcome of pneumococcal infection in SCD. In this study, we tested this hypothesis in an experimental SCD mouse model and found that statin therapy prolonged survival following pneumococcal challenge. The protective effect resulted in part from decreased platelet-activating factor receptor expression on endothelia and epithelia, which led to reduced bacterial invasion. An additional protective effect resulted from inhibition of host cell lysis by pneumococcal cholesterol-dependent cytotoxins (CDCs), including pneumolysin. We conclude therefore that statins may be of prophylactic benefit against invasive pneumococcal disease in patients with SCD and, more broadly, in settings of bacterial pathogenesis driven by receptor-mediated endocytosis and the CDC class of toxins produced by Gram-positive invasive bacteria.

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“…34 Alterations in expression levels of multiple TLRs in the mouse brain during aging have also been reported. 35 Changes in MyD88 expression levels during aging may contribute to A␤ load in the brain.…”

Section: Myd88 Expression Decreases During Agingmentioning

confidence: 98%

MyD88 Deficiency Ameliorates β-Amyloidosis in an Animal Model of Alzheimer's Disease

Lim

Kou

Song

et al. 2011

The American Journal of Pathology

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The accumulation of ␤-amyloid protein (A␤) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD).Accumulation of aggregated ␤-amyloid protein (A␤) in the brain is postulated to be a causal event in the etiology of Alzheimer's disease (AD). 1 Fibrillar A␤ deposits in the brain are accompanied by activated microglia.2 Increasing lines of evidence support the notion that activated microglia play pivotal dual roles in AD progression: either clearing A␤ deposits by phagocytosis and promoting neuronal survival and plasticity or releasing cytotoxic molecules and proinflammatory cytokines, exacerbating A␤ load and neurodegeneration.3-5 Fibrillar A␤ can activate microglia through interaction with cell surface receptor complexes, resulting in its phagocytosis and inflammatory responses. Some toll-like receptors (TLRs), including TLR2, TLR4, and TLR6, have been shown to be essential components of the receptor complexes for microglial activation by A␤. 6 -8 TLRs are a class of patternrecognition receptors in the innate immune system. One of the important roles of TLRs is to activate phagocytes/ microglia in response to insults, including pathogens and damaged host cells, and to clear pathogens, damaged tissues, and accumulated wastes. Stimulation of TLR4 by lipopolysaccharide, a TLR4 ligand, has been repeatedly demonstrated to activate microglia in the brain. 4 Hippocampal or intraperitoneal injection of lipopolysaccharide in old AD mouse models decreased diffuse A␤ plaques but not fibrillar A␤ plaques.9 -12 Injection of CpG oligodeoxynucleotide, a TLR9 ligand, reduced A␤ load in the brain and restored cognitive deficits in an AD mouse model. 13,14 Furthermore, a functionally inactive mutation in the TLR4 gene caused an increase in A␤ load in the brain of an AD mouse model. 15 These results suggest that activation of TLRs can be a therapeutic option for AD. On the other hand, repeated injections of lipopolysaccharide induced premature fibrillar A␤ deposits in young AD

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

Cited by 135 publications

References 47 publications

Impaired Innate Mucosal Immunity in Aged Mice Permits Prolonged Streptococcus pneumoniae Colonization

Impaired Innate Mucosal Immunity in Aged Mice Permits Prolonged Streptococcus pneumoniae Colonization

Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease

MyD88 Deficiency Ameliorates β-Amyloidosis in an Animal Model of Alzheimer's Disease

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