Differential Gene Expression of Interleukin-1 Receptor Associated Kinase-1 and Interleukin-1 Receptor Associated Kinase-M in Peripheral Blood Mononuclear Cells of Young and Aged Rats Following Preconditioning With Endotoxin

Li, Yingzhe; Howell, Elizabeth A.; Lagoo, Anand S.; Kuchibhatla, Maragatha; Pan, Hongjie; Cohen, Harvey Jay; Lagoo, Sandhya A.

doi:10.1097/shk.0b013e3181778ab2

Cited by 15 publications

(12 citation statements)

References 36 publications

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“…In circulating neutrophil populations, human studies suggest that expression of TLR2 and TLR4 are unaltered with age, though membrane-associated MyD88 was decreased with age after exogenous stimulation with LPS (11). Though not evaluated in our study, age-associated alterations in TLR2 signaling pathways, such as MyD88, may dampen TLR2 responses in aged individuals and contribute to delayed resolution of bacterial infection (72–74). …”

Section: Discussionmentioning

confidence: 94%

Reduced Neutrophil Chemotaxis and Infiltration Contributes to Delayed Resolution of Cutaneous Wound Infection with Advanced Age

Brubaker

Rendón

Ramírez

et al. 2013

The Journal of Immunology

144

108

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Advanced age is associated with alterations in innate and adaptive immune responses, which contribute to an increased risk of infection in elderly patients. Coupled with this immune dysfunction, elderly patients demonstrate impaired wound healing with elevated rates of wound dehiscence and chronic wounds. To evaluate how advanced age alters the host immune response to cutaneous wound infection, we developed a murine model of cutaneous Staphylococcus aureus wound infection in young (3–4 month) and aged (18–20 month) BALB/c mice. Aged mice exhibit increased bacterial colonization and delayed wound closure over time compared to young mice. These differences were not attributed to alterations in wound neutrophil or macrophage TLR2 or FcγRIII expression, or age-related changes in phagocytic potential and bactericidal activity. To evaluate the role of chemotaxis in our model, we first examined in vivo chemotaxis in the absence of wound injury to KC, a neutrophil chemokine. In response to a subcutaneous injection of KC, aged mice recruited fewer neutrophils at increasing doses of KC compared to young mice. This paralleled our model of wound infection, where diminished neutrophil and macrophage recruitment was observed in aged mice relative to young mice despite equivalent levels of KC, MIP-2 and MCP-1 chemokine levels at the wound site. This reduced leukocyte accumulation was also associated with lower levels of ICAM-1 in wounds from aged mice at early time points. These age-mediated defects in early neutrophil recruitment may alter the dynamics of the inflammatory phase of wound healing, impacting macrophage recruitment, bacterial clearance and wound closure.

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Section: Discussionmentioning

confidence: 94%

Reduced Neutrophil Chemotaxis and Infiltration Contributes to Delayed Resolution of Cutaneous Wound Infection with Advanced Age

Brubaker

Rendón

Ramírez

et al. 2013

The Journal of Immunology

144

108

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“…Several studies have implicated the IL-1 receptor–associated kinase (IRAK) family in the regulation of LPS tolerance. Models of endotoxemia have demonstrated up-regulation of IRAK-M (produced by monocytes) and down-regulation of IRAK-1 in LPS preconditioned peripheral blood mononuclear cells restimulated with LPS (25). It is possible that IRAK-M down-regulation plays a role in suppression of macrophage TNF-α in this model.…”

Section: Discussionmentioning

confidence: 99%

Chronic Pulmonary LPS Tolerance Induces Selective Immunosuppression While Maintaining the Neutrophilic Response

Natarajan¹,

Kim²,

Remick³

2010

Shock

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LPS challenge causes potent activation of innate immunity. Because LPS is ubiquitously present in ambient air, repeated inhalation may lead to activation of the pulmonary immune response. If this activation is unregulated, chronic LPS inhalation would lead to persistent inflammation and organ damage. We hypothesized that the lung uses the mechanism of LPS tolerance to maintain the balance between hypoinflammatory and hyperinflammatory states. We developed a model of chronic pulmonary LPS tolerance induced by pulmonary exposure to 1 μg LPS for 4 consecutive days. Mice were challenged with 10 μg of LPS 24 h later. TNF-α protein was significantly decreased in the bronchoalveolar lavage fluid of tolerant versus nontolerant mice, whereas IL-6 levels were significantly increased in the tolerant group. Tolerant mice were also protected from airway hyperresponsiveness. M2 and M3 muscarinic receptor mRNA was significantly decreased in the lungs of tolerant mice, suggesting a mechanism for the decreased airway hyperresponsiveness. CXCL2 was significantly reduced in tolerant mice, but CXCL1 was equivalent between groups. No difference was seen in neutrophil recruitment to the alveolar space. Interestingly, LPS tolerance does not confer cross-tolerance to the Toll-like receptor (TLR) 2 stimulus Pam3Cys. TNF-α and IL-6 concentrations were significantly increased in LPS-tolerant mice challenged with Pam3Cys; however, chemokine concentrations were unaffected. Our data show that repeated LPS inhalation results in differential regulation of cytokines but does not inhibit neutrophil recruitment. This unrestricted neutrophil recruitment may represent a mechanism by which individuals may be protected from pulmonary bacterial infection and pneumonia.

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“…Increased levels of IRAK‐M mRNA have been observed with increased age in mice [57]. During TLR signalling, IRAK‐1 associates with TRAF6 resulting in activation via phosphorylation.…”

Section: Suppressors Of Tlr Signalling In Agementioning

confidence: 99%

The effect of ageing on macrophage Toll-like receptor-mediated responses in the fight against pathogens

Dunston

Griffiths

2010

Clinical and Experimental Immunology

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SummaryThe cellular changes during ageing are incompletely understood yet immune system dysfunction is implicated in the age-related decline in health. The acquired immune system shows a functional decline in ability to respond to new pathogens whereas serum levels of cytokines are elevated with age. Despite these age-associated increases in circulating cytokines, the function of aged macrophages is decreased. Pathogen-associated molecular pattern receptors such as Toll-like receptors (TLRs) are vital in the response of macrophages to pathological stimuli. Here we review the evidence for defective TLR signalling in normal ageing. Gene transcription, protein expression and cell surface expression of members of the TLR family of receptors and co-effector molecules do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signalling events, including inhibition of positive and activation of negative modulators of TLR induced signalling events. In this paper we hypothesize that despite a poor inflammatory response via TLR activation, the ineffective clearance of pathogens by macrophages increases the duration of their activation and contributes to perpetuation of inflammatory responses and ageing.

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Differential Gene Expression of Interleukin-1 Receptor Associated Kinase-1 and Interleukin-1 Receptor Associated Kinase-M in Peripheral Blood Mononuclear Cells of Young and Aged Rats Following Preconditioning With Endotoxin

Cited by 15 publications

References 36 publications

Reduced Neutrophil Chemotaxis and Infiltration Contributes to Delayed Resolution of Cutaneous Wound Infection with Advanced Age

Reduced Neutrophil Chemotaxis and Infiltration Contributes to Delayed Resolution of Cutaneous Wound Infection with Advanced Age

Chronic Pulmonary LPS Tolerance Induces Selective Immunosuppression While Maintaining the Neutrophilic Response

The effect of ageing on macrophage Toll-like receptor-mediated responses in the fight against pathogens

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