TLR2
Toll-like receptor 2 precursor (EC 3.2.2.6) (Toll/interleukin-1 receptor-like protein 4) (CD282 antigen) [TIL4]
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Soluble toll-like receptor-2 (sTLR2) and soluble CD14 (sCD14) in saliva are defense proteins that bind specific microbe-associated molecular patterns. Since the oral flora changes with aging, the objective of this study is to determine and compare the concentration of sTLR2 and sCD14 in the saliva of healthy individuals in age groups from the first to the sixth decade of life. Unstimulated whole saliva was collected after obtaining informed consent. The concentration of sCD14 and sTLR-2 was measured by enzyme-linked immunosorbent assay. Statistical differences between the age groups were determined by analysis of variance. The relationship between the two markers in each age group was evaluated by Pearson's correlation coefficient and linear regression analyses. The concentration of salivary sTLR2 was highest in the youngest, and that of the sCD14 was highest in the oldest age group. While the salivary sCD14 and the sTLR2 exhibited a moderate negative correlation in the youngest, the relationship between the two markers was inversed in the oldest age group. The results of our exploratory study suggest a need to adjust for age-dependent changes in sCD14 and sTLR2 in healthy saliva while assessing the two proteins as biomarkers.
MeSH Terms
- Adolescent
- Adult
- Aging
- Biomarkers
- Child
- Child, Preschool
- Humans
- Lipopolysaccharide Receptors
- Middle Aged
- Saliva
- Salivary Proteins and Peptides
- Toll-Like Receptor 2
- Young Adult
Keywords
- Age changes
- CD14
- Saliva
- Toll-like receptor-2
The bovine genes TLR1, TLR2 and TLR6, which encode Toll-like receptors, key components of the innate immune system, were screened for polymorphisms in Czech Red Pied (Czech Simmental) cattle, and the different variants present in the population were tested for association with reproductive and fitness traits. Diversity was investigated in a group of 164 bulls using hybrid resequencing of pooled amplicons with PacBio technology and of pooled genomic DNA using HiSeq X-Ten technology. The validated single nucleotide polymorphisms (SNPs) were genotyped in individual animals using the primer extension technique. The association of genotypic classes of 16 polymorphisms with six phenotypic traits were estimated with one-way analysis of variance (ANOVA) and with restricted maximum likelihood (REML) algorithm. The evaluated traits included the incidence of cystic ovaries, index of early reproductive disorders, paternal and maternal indicators of calving ease, production longevity and calf vitality index. The estimated breeding values were used for combined trait quantification. Early traits, namely, cystic ovaries and early reproductive disorders, were not associated with any of the tested polymorphisms according to the general ANOVA test. By contrast, five variants of all three genes were associated with calving ease, both paternal and maternal. The production longevity correlated with two variants of TLR1 and the calf vitality index correlated with the 1044 T > C (rs68268249) polymorphism in TLR2. The false discovery rate (FDR) according to Benjamini-Hochberg was favourable for the calving ease trait (0.221) and maternal calving ease (0.214), which allows to consider the observed associations real, regardless of the error arising from the multiple comparisons. These results were supported by REML only partially, probably in view of the additivity assumption. Two mechanisms of action on calving are conceivable, either via infection resistance or via the involvement of TLR2 in signalling in the myometrium. The known formation of heterodimers by the TLR1, -2 and -6 products might be responsible for the shared pattern of action in these genes. The association of the calf vitality index with TLR2 variation might reflect the increased role of infections in calves compared to adult animals.
MeSH Terms
- Age Factors
- Animals
- Breeding
- Cattle
- Czech Republic
- Female
- Genotype
- Longevity
- Male
- Phenotype
- Polymorphism, Single Nucleotide
- Reproduction
- Toll-Like Receptor 1
- Toll-Like Receptor 2
- Toll-Like Receptor 6
- Toll-Like Receptors
Keywords
- Cattle
- Diversity
- Effect prediction
- Health traits
- Toll-like receptors
While there are murine and rat choroid plexus epithelial cell cultures, a translationally relevant model for choroid plexus activation and function is still lacking. The rhesus macaque is the gold standard for modeling viral infection and activation of CNS, including HIV-associated neurocognitive disorders. We have developed a rhesus macaque choroid plexus epithelial cell culture model which we believe to be suitable for studies of inflammation associated with viral infection of the CNS. Epithelial morphology and function were assessed using vimentin, phalloidin, the tight junction protein zonula-occludens-1 (ZO-1), and focal adhesion kinase (FAK). Choroid plexus epithelial cell type was confirmed using immunofluorescence with two proteins highly expressed in the choroid plexus: transthyretin and α-klotho. Finally, barrier properties of the model were monitored using pro- and anti-inflammatory mediators (TNF-α, the TLR2 agonist PamCys3K, and dexamethasone). When pro-inflammatory TNF-α was added to the xCelligence wells, there was a decrease in barrier function, which decreased in a step-wise fashion with each additional administration. This barrier function was repaired upon addition of the steroid dexamethasone. The TLR2 agonist PAM3CysK increased barrier functions in TNF-α treated wells. We have presented a model of the blood-CSF barrier that will allow study into pro- and anti-inflammatory conditions in the brain, while simultaneously measuring real time changes to epithelial cells.
Keywords
- aging
- cell culture
- choroid plexus
- epithelial cell
- infectious disease
- rhesus macaque
To determine whether term fetal membranes from transabdominal cerclage (TAC) patients have favorable characteristics compared with membranes from patients without TAC. A prospective study of consecutive pregnant women who had undergone TAC and were delivered by elective cesarean after 37 weeks before the onset of labor at Cliniques universitaires Saint-Luc, Brussels, between January 2015 and June 2016. Membranes were collected from two areas: overlying the cervix and located far from the cervix. Membrane thickness, 15-hydroxyprostaglandin dehydrogenase (PGDH), toll-like receptor-2 (TLR2) expression, and senescence were measured and compared between the TAC group and a control group without TAC enrolled using the same study criteria. In the cervical area of the TAC group, the chorion was significantly thicker (P=0.003). PGDH and TLR2 expression were also significantly increased in the cervical area of the TAC group (P=0.021 and P=0.043, respectively). Senescence was significantly decreased in the TAC group (P=0.001). A significant relationship between chorion thickening and increase in PGDH and TLR2 expression and decrease in senescence was reported in the cervical area of membranes in the TAC group. These membrane changes could prevent triggering of parturition and may account for favorable outcomes and clinical success in pregnancies with TAC.
MeSH Terms
- Adult
- Case-Control Studies
- Cerclage, Cervical
- Cesarean Section
- Chorion
- Extraembryonic Membranes
- Female
- Humans
- Hydroxyprostaglandin Dehydrogenases
- Pregnancy
- Prospective Studies
- Uterine Cervical Incompetence
Keywords
PGDH
- Cellular senescence
- Cervical insufficiency
- Chorioamniotic membranes
- Fetal membranes
- TLRs
- Transabdominal cerclage
- Zone of altered morphology
Sepsis is more common in the elderly. TNF⍺ is recognized as an important mediator in sepsis and Toll-like receptors (TLRs) play an important role in initiating signaling cascades to produce TNF⍺. Little is known about how innate immunity is altered in healthy human aging that predisposes to sepsis. We tested the hypothesis that aging dysregulates the innate immune response to TLR 2 and 4 ligands. We performed whole blood assays on 554 healthy subjects aged 40-80 years. TNFα production was measured at baseline and after stimulation with the TLR2 agonists: peptidoglycan, lipoteichoic acid, Pam3CysK, Zymosan A and the TLR4 agonist lipopolysaccharide (LPS). In a subset of subjects (n = 250), we measured Toll-like receptor (TLR) 2, 4 and MyD88 expression using real-time PCR. We measured a 2.5% increase per year in basal secretion of TNFα with aging (n = 554 p = 0.02). Likewise, TNFα secretion was increased with aging after stimulation with peptidoglycan (1.3% increase/year; p = 0.0005) and zymosan A (1.1% increase/year p = 0.03). We also examined the difference between baseline and stimulated TNFα for each individual. We found that the increase was driven by the elevated baseline levels. In fact, there was a diminished stimulated response to LPS (1.9% decrease/year; p = 0.05), lipoteichoic acid (2.1% decrease/year p = 0.03), and Pam3CysK (2.6% decrease/year p = 0.0007). There were no differences in TLR or MyD88 mRNA expression with aging, however, there was an inverse relationship between TLR expression and stimulated TNFα production. With aging, circulating leukocytes produce high levels of TNFα at baseline and have inadequate responses to TLR2 and TLR4 agonists. These defects likely contribute to the increased susceptibility to sepsis in older adults.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Humans
- Immunity, Innate
- Middle Aged
- Sepsis
- Signal Transduction
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Tumor Necrosis Factor-alpha
Keywords
- Aging
- Immunosenescence
- Inflammaging
- Innate immunity
- Sepsis
- Shock
- TLR signaling
- TNFα
Aging is an inevitable physiological challenge occurring in organisms over time, and is also the most important risk factor of neurodegenerative diseases. In this study, we observed cellular and molecular changes of different age mice and LPS-induced Parkinson disease (PD) model. The results showed that behavioral performance and dopaminergic (DA) neurons were declined, accompanied by increased expression of pro-inflammatory factors (TLR2, p-NF-kB-p65, IL-1β and TNF-α), as well as pro-oxidative stress factor gp91phox in aged mice compared with young mice. Aging exaggerated inflammatory M1 microglia, and destroyed the balance between oxidation and anti-oxidation. The intranasal LPS instillation induced PD model in both young and aged mice. The poor behavioral performance and the loss of DA neurons as well as TLR2, p-NF-kB-p65, IL-1β, TNF-α, iNOS and gp91phox were further aggravated in LPS-aged mice. Interestingly, the expression of Nrf2 and HO-1 was up-regulated by LPS only in young LPS-PD mice, but not in aged mice. The results indicate that the synergy of aging process and LPS exposure may prominently aggravate the DA neurons loss caused by more serious neuroinflammation and oxidative stress in the brain.
Keywords
- Aging
- Lipopolysaccharides
- Parkinson’s disease
- neuroinflammation
- oxidative stress
As the crucial etiological factor, aging-related microglia activation promotes the development of Parkinson's disease (PD). However, the molecular and functional changes of aged-microglia and their contribution to neurodegeneration in PD are only partially understood, which was investigated in our study. Female C57BL/6 mice were randomly divided into four groups, included young-control group, young-MPTP group, aged-control group and aged-MPTP group. Pole test and adhesive removal test were firstly performed. ELISA assay was used to detect the content of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) in brain tissue. Then we tested the expression of tyrosine hydroxylase (TH), p-nuclear transcription factor (NF-κB), toll-like receptor2 (TLR2), arginase-1 (arg-1), inducible nitric oxide synthase (iNOS) by western blot and immunofluorescence analysis. Our results showed that aging promoted M1 microglia activation and inhibited M2 microglia activation in SN in MPTP-PD model, accompanied by the elevation of proinflammatory cytokine (TNF-α and IL-1β). Consequently, aging significantly aggravated motor dysfunction and dopaminergic neuron loss in SN. Besides, compared with young-MPTP group, the protein expression of TLR2 and p-NF-κB-p65 increased obviously in aged-MPTP group. The results revealed that aging aggravated inflammatory response by modulated microglia phenotypes transition in SN in PD, and contributed to further understand the pathogenesis of PD.
MeSH Terms
- Aging
- Animals
- Disease Models, Animal
- Dopamine
- Dopaminergic Neurons
- Female
- Interleukin-1beta
- MPTP Poisoning
- Mice
- Mice, Inbred C57BL
- Microglia
- Nitric Oxide Synthase Type II
- Parkinson Disease, Secondary
- Phenotype
- Transcription Factor RelA
- Tumor Necrosis Factor-alpha
- Tyrosine 3-Monooxygenase
Keywords
- Aging
- NF-κB
- Neuroinflammation
- Parkinson's disease
- TLR2
Toll-like receptors (TLRs) are a family of pattern-recognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied aging-associated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8- and 12-month-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-month-old TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Mechanistically, TLR2 deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor Forkhead box protein O1 (FoxO1) and, in turn, to elevated expression of FoxO target genes involved in the regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling while improving the contractile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and the activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice.
MeSH Terms
- Aging
- Animals
- Cells, Cultured
- Forkhead Box Protein O1
- Gene Expression Regulation
- Heart Diseases
- Macrophages
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myocytes, Cardiac
- Phosphatidylinositol 3-Kinases
- Signal Transduction
- Toll-Like Receptor 2
Keywords
- FOXO
- aging
- cardiovascular disease
- fibrosis
- muscle atrophy
- toll-like receptor (TLR)
Immunophenotyping by multi-color flow cytometry is arguably the best tool to identify and quantify distinct cell lineages from the peripheral blood and other biological fluids/tissues. Effective in both clinical and research settings, it can be used to estimate the frequency of a given cell type or measure its phenotypic or functional properties. Normally, immunophenotyping is performed in fresh or fractionated blood (i.e., PBMCs) the same day, or within 24 hours of collection; however, this may not be feasible for all study designs. We have previously shown that cryopreserved blood, a biospecimen that is simple and inexpensive to prepare, is comparable to fresh blood for the enumeration of major leukocyte cell types. For the following study, we sought to extend these observations to distinct subsets of: monocytes (classical, intermediate, and non-classical), T-cells (CD4/CD8 naïve, central and effector memory, senescent, and terminally differentiated, and regulatory T-cells), and NK-cells (CD56 bright and dim); we also examined the expression of monocyte cell-surface receptors CX3CR1, CCR2, TLR2, and TLR4. Our results indicate that cryopreserved blood is comparable to fresh blood; with exception to relatively rare subsets and lowly expressed receptors, the absolute or relative frequency of cell subsets generally correlated >0.80 between blood types, while monocyte receptor expressed was mostly >0.70. Furthermore, the day-to-day coefficient of variation for most cell subsets and parameters was below 20%. Given these findings, we suggest that cryopreserved peripheral blood be given greater consideration for studies in which the quantification of distinct leukocyte subsets is required. © 2018 International Society for Advancement of Cytometry.
MeSH Terms
- Aged
- Aged, 80 and over
- Canada
- Cryopreservation
- Female
- Flow Cytometry
- Humans
- Immunophenotyping
- Killer Cells, Natural
- Longitudinal Studies
- Lymphocyte Subsets
- Male
- Middle Aged
- Monocytes
- T-Lymphocytes
Keywords
- Canadian Longitudinal Study on Aging (CLSA)
- T-cells
- blood
- flow cytometry
- immunophenotyping
- monocytes
- natural killer cells
- regulatory T-cells
Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by loss of dopaminergic neurons associated with neuroinflammation. Toll-like receptors (TLRs) are expressed in peripheral blood leukocytes and also in neurons and glial cells mediating inflammation. This study aimed to investigate the peripheral blood leukocyte response to TLR2 and TLR4 agonists in young and elderly PD patients. Two groups of patients with PD were evaluated (≤ 55 years old and ≥ 65 years old), age-matched with healthy controls (n = 26). Severity of PD was evaluated by Unified Parkinson's Disease Rating Scale (UPDRS). Whole blood cultures were stimulated with lipopolysaccharide (LPS), a TLR4 agonist or Pam Cys (Pam), a TLR2 agonist. Tumor necrosis factor alpha (TNFα) and interleukin 10 (IL-10) were measured by immunoenzimatic assay. 6 h-TNFα production was increased after TLR4 stimulation, mainly in young PD patients, whereas TLR2-induced TNFα and IL-10 levels were decreased in PD patients independent of age (p < 0.05). A reverse correlation between LPS-induced TNFα production and age was observed in PD patients and controls, but TNFα induced by TLR2 agonist was not associated with age of PD patients or controls. TNFα production induced by TLR4 but not by TLR2 was reversely associated with the age at PD onset and disease duration. No associations between UPDRS scores and cytokine levels were detected. In conclusion, TLR4 and TLR2 responses seem to be differentially affected during PD. Data suggest that TLR2 deficiency in periphery is independent of age of the patients, age at PD onset, or PD duration.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Cells, Cultured
- Humans
- Interleukin-10
- Lipopolysaccharides
- Lipoproteins
- Middle Aged
- Parkinson Disease
- Risk
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Tumor Necrosis Factor-alpha
Keywords
- Parkinson’s disease
- Whole blood cultures
- aging
- cytokines
- toll-like receptors
Aging is associated with chronic inflammation partly mediated by increased levels of damage-associated molecular patterns, which activate pattern recognition receptors (PRRs) of the innate immune system. Furthermore, many aging-related disorders are associated with inflammation. PRRs, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs), are expressed not only in cells of the innate immune system but also in other cells, including cells of the neurovascular unit and cerebral vasculature forming the blood-brain barrier. In this review, we summarize our present knowledge about the relationship between activation of PRRs expressed by cells of the neurovascular unit-blood-brain barrier, chronic inflammation, and aging-related pathologies of the brain. The most important damage-associated molecular pattern-sensing PRRs in the brain are TLR2, TLR4, and NLR family pyrin domain-containing protein-1 and pyrin domain-containing protein-3, which are activated during physiological and pathological aging in microglia, neurons, astrocytes, and possibly endothelial cells and pericytes.
MeSH Terms
- Age Factors
- Aging
- Animals
- Blood-Brain Barrier
- Humans
- Immunity, Innate
- Inflammasomes
- Inflammation
- Microvessels
- NLR Proteins
- Neurovascular Coupling
- Receptors, Pattern Recognition
- Signal Transduction
- Toll-Like Receptor 2
- Toll-Like Receptor 4
Keywords
- aging
- blood-brain barrier
- damage-associated molecular patterns
- inflammasome
- pattern recognition receptors
Cellular senescence is associated with aging and is considered a potential contributor to age-associated neurodegenerative disease. Exposure to ionizing radiation increases the risk of developing premature neurovascular degeneration and dementia but also induces premature senescence. As cells of the cerebrovascular endothelium are particularly susceptible to radiation and play an important role in brain homeostasis, we investigated radiation-induced senescence in brain microvascular endothelial cells (EC). Using biotinylation to label surface proteins, streptavidin enrichment and proteomic analysis, we analyzed the surface proteome of stress-induced senescent EC in culture. An array of both recognized and novel senescence-associated proteins were identified. Most notably, we identified and validated the novel radiation-stimulated down-regulation of the protease, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 is an important modulator of amyloid beta protein production, accumulation of which is central to the pathologies of Alzheimer's disease and cerebral amyloid angiopathy. Concurrently, we identified and validated increased surface expression of ADAM10 proteolytic targets with roles in neural proliferation and survival, inflammation and immune activation (L1CAM, NEO1, NEST, TLR2, DDX58). ADAM10 may be a key molecule linking radiation, senescence and endothelial dysfunction with increased risk of premature neurodegenerative diseases normally associated with aging.
MeSH Terms
- ADAM10 Protein
- Amyloid Precursor Protein Secretases
- Animals
- Autophagy
- Biotinylation
- Capillaries
- Cell Proliferation
- Cell Survival
- Cellular Senescence
- Down-Regulation
- Endothelial Cells
- Membrane Proteins
- Mice
- Neurons
- Proteomics
- Radiation, Ionizing
- Stress, Physiological
- alpha-Galactosidase
Keywords
- ADAM10
- biotinylation
- endothelial cells
- ionizing radiation
- senescence
Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.
MeSH Terms
- Aging
- Animals
- Autophagy
- Autophagy-Related Protein 5
- Cells, Cultured
- Extracellular Traps
- Immunity, Innate
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neutrophil Activation
- Neutrophils
- Reactive Oxygen Species
- Toll-Like Receptor 2
Keywords
- Atg5
- aging
- apoptosis
- autophagy
- neutrophil extracellular traps
Aging is associated with a range of chronic low-grade inflammation (Chronoinflammaging) which may play a significant role in some chronic inflammatory based diseases, such as Alzheimer disease (AD). However, the events which lead to the induction of chronoinflammaging in AD are yet to be clarified. It has been proposed that the recognition of endogenous ligands by pathogen recognition receptors (PRRs) may be involved in the induction of chronoinflammaging. Toll like receptors (TLRs) are a family of PRRs which recognize endogenous damage associated molecular patterns (DAMPs) and subsequently induce inflammation. Therefore, TLRs are worthy of investigation to elucidate their roles in chronoinflammaging associated AD. This review article explores the main roles played by TLR2 in the pathogenesis of chronoinflammaging in patients suffering from AD.
MeSH Terms
- Alzheimer Disease
- Chronic Disease
- Humans
- Inflammation
- Toll-Like Receptor 2
Keywords
- Aging
- Alzheimer
- Inflammation
- TLR2
Organ transplantation in older people is increasing, but how aging impacts B-cell responses to organ transplantation is still unknown. Here, we show that the depletion of B cells with anti-CD20 antibodies has disparate effects depending on recipient age. In young murine recipients, anti-CD20 treatment impaired the ability of immune modulation to extend skin allograft survival. In contrast, anti-CD20 treatment extended allograft survival in aged recipients treated with immune modulation. Although regulatory B-cell function and the numbers of marginal and follicular B cells were similar between age groups, a subpopulation of B cells, termed age-associated B cells (ABCs), accumulated upon aging. ABCs isolated from aged mice exhibited upregulation of CD73, CD80, CD106, and TLR2 and an increased capacity to augment T-cell alloimmunity compared to ABCs from young mice. Importantly, ABCs from aged, but not young, mice impaired the ability of immune modulation to enhance allograft survival after adoptive transfer into young transplant recipients. Our study indicates that ABCs impair the immune regulation of allografts. Thus, recipient age needs to be considered when proposing B-cell-depleting immune therapy.
MeSH Terms
- 5'-Nucleotidase
- Adoptive Transfer
- Aging
- Allografts
- Animals
- Antibodies, Monoclonal
- B-Lymphocytes
- B7-1 Antigen
- Graft Rejection
- Graft Survival
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Skin Transplantation
- Toll-Like Receptor 2
- Transplantation, Homologous
- Vascular Cell Adhesion Molecule-1
Keywords
- Aging
- Animal models
- B cells
- Immune regulation
- Transplantation
Estrogens are known to exert neuroprotective and immuneomodulatory effects after stroke. However, at present, little is known about the role of estrogens and its receptors in postischemic inflammation after menopause. Here, we provide important in vivo evidence of a distinct shift in microglial phenotypes in the model of postmenopause brain. Using a model-system for live imaging of microglial activation in the context of chronic estrogen- and ERα-deficiency associated with aging, we observed a marked deregulation of the TLR2 signals and/or microglial activation in ovariectomized and/or ERα knockout mice. Further analysis revealed a 5.7-fold increase in IL-6, a 4.7-fold increase in phospho-Stat3 levels suggesting an overactivation of JAK/STAT3 pathway and significantly larger infarction in ERα knockouts chronically deprived of estrogen. Taken together, our results suggest that in the experimental model of menopause and/or aging, ERα mediates innate immune responses and/or microglial activation, and ischemia-induced production of IL-6. Based on our results, we propose that the loss of functional ERα may lead to deregulation of postischemic inflammatory responses and increased vulnerability to ischemic injury in aging female brains.
MeSH Terms
- Aging
- Animals
- Brain
- Brain Ischemia
- Estrogen Receptor alpha
- Estrogens
- Female
- Immunity, Innate
- Interleukin-6
- Menopause
- Mice, Inbred C57BL
- Mice, Transgenic
- Microglia
- Models, Animal
- STAT3 Transcription Factor
Keywords
- Galectin-3
- IL-6
- Menopause
- Microglia
- Neruoinflammation
- Stroke
- TLR2
Autophagy is a molecular process essential for the maintenance of cellular homeostasis, which appears to (i) decline with age and (ii) respond to physical exercise. In addition, recent evidence suggests a crosstalk between autophagy and toll-like receptor (TLR)-associated inflammatory responses. This study assessed the effects of aerobic exercise training on autophagy and TLR signaling in older subjects. Twenty-nine healthy women and men (age, 69.7 ± 1.0 year) were randomized to a training (TG) or a control (CG) group. TG performed an 8-week aerobic training program, while CG followed their daily routines. Peripheral blood mononuclear cells were isolated from blood samples obtained before and after the intervention, and protein levels of protein 1 light chain 3 (LC3), sequestosome 1 (p62/SQSTM1), beclin-1, phosphorylated unc-51-like kinase (ULK-1), ubiquitin-like autophagy-related (Atg)12, Atg16, and lysosome-associated membrane protein (LAMP)-2 were measured. TLR2 and TLR4 signaling pathways were also analyzed. Peak oxygen uptake increased in TG after the intervention. Protein expression of beclin-1, Atg12, Atg16, and the LC3II/I ratio increased following the training program (p < 0.05), while expression of p62/SQSTM1 and phosphorylation of ULK-1 at Ser(757) were lower (p < 0.05). Protein content of TLR2, TLR4, myeloid differentiation primary response gen 88 (MyD88), and TIR domain-containing adaptor-inducing interferon (TRIF) were not significantly modified by exercise. The current data indicate that aerobic exercise training induces alterations in multiple markers of autophagy, which seem to be unrelated to changes in TLR2 and TLR4 signaling pathways. These results expand knowledge on exercise-induced autophagy adaptations in humans and suggest that the exercise type employed may be a key factor explaining the potential relationship between autophagy and TLR pathways.
MeSH Terms
- Adult
- Aged
- Aging
- Autophagy
- Biomarkers
- Blotting, Western
- Female
- Humans
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Physical Fitness
- Signal Transduction
- Toll-Like Receptor 4
- Young Adult
Keywords
- Autophagy
- Elderly
- High-intensity interval training
- TLR
Human aging is associated with remodeling of the immune system. While most studies on immunosenescence have focused on adaptive immunity, the effects of aging on innate immunity are not well understood. Here, we investigated whether aging affects cytokine responses to a wide range of well-defined pattern recognition receptor (PRR) ligands, such as ligands for Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), retinoic-acid-inducible gene-I like receptors (RLRs) and the cytosolic DNA sensor absent in melanoma 2 (AIM2). Blood was collected from 16 young (20-39 years) and 18 elderly (60-84 years) healthy participants. Pro-inflammatory cytokine (TNF-α, IL-1β, IL-6, and IL-8) production in a whole blood assay (WBA) after stimulation with TLR ligands (Pam3csk4, poly(I:C), LPS, CpG), CLR ligand (β-glucan), NLR ligand (MDP), RLR ligands (5'ppp-dsDNA and poly(I:C)/lyovec) and the AIM2 ligand (poly(dA:dT) was assessed by ELISA. TLR2 and TLR4 expression by leukocytes and monocytes was determined by flow-cytometry. Expression of AIM2 by peripheral blood mononuclear cells (PBMC) was assessed by qRT-PCR and Western blot. Cytokine responses to Pam3csk4, poly(I:C) and CpG, β-glucan, MDP, 5'ppp-dsDNA and poly(I:C)/lyovec were comparable between young and old participants. We observed a higher IL-8 response following stimulation of elderly blood samples with the TLR4 ligand LPS, which was associated with higher proportions of TLR4 expressing monocytes. Interestingly, stimulation of whole blood cells with the AIM2 ligand poly(dA:dT) resulted in significantly lower cytokine responses in old participants. Moreover, these lower cytokine responses were associated with lower AIM2 protein expression and activation in PBMC of old participants. Our findings reveal an age-dependent reduction of AIM2 expression and activation which may explain reduced cytokine responses to the cytosolic DNA mimic poly(dA:dT) in healthy elderly individuals. Reduced AIM2-mediated sensing with age may contribute to increased vulnerability to bacterial or viral infections in the elderly.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cytokines
- DNA-Binding Proteins
- Female
- Humans
- Male
- Middle Aged
- Monocytes
- Signal Transduction
- Toll-Like Receptors
- Young Adult
Keywords
- Absent in melanoma 2
- Aging
- Human
- Innate immunity
- Pattern recognition receptors
Streptococcus pneumoniae is a complex Gram-positive bacterium comprising over 90 different serotypes and is a major cause of pneumonia. Susceptibility to S. pneumoniae is remarkably age-related being greatest in children under 5 years old and adults over 65. Whilst the immaturity of the immune system is largely responsible for poor immunity in the former, the underlying causes of susceptibility in older adults is complex. Immunity to S. pneumoniae is mediated predominantly through the inflammatory response in the nasopharyngeal mucosa recruiting phagocytes (neutrophils and monocyte/macrophages) which recognise the pathogen via TLR2 and ingest and kill the bacteria, with the induction of Th17 cells being required to maintain neutrophil recruitment and ensure clearance of the infection. In this review we discuss the impact of ageing upon these aspects of immunity to S. pneumoniae, as well as age-related changes to the serotypes present in the adult nasopharyngeal tract which could further influence susceptibility to infection.
MeSH Terms
- Aging
- Disease Susceptibility
- Evidence-Based Medicine
- Humans
- Immunity, Innate
- Immunosenescence
- Models, Immunological
- Pneumococcal Infections
Keywords
- Ageing
- Immunesenescence
- Pneumonia
- Streptococcus pneumoniae
Monocytes are mediators of the inflammatory response and include three subsets: classical, intermediate, and nonclassical. Little is known about the phenotypical and functional age-related changes in monocytes and their association with soluble inflammatory biomarkers, cytomegalovirus infection, and functional and mental decline. We assayed the activation ex vivo and the responsiveness to TLR2 and TLR4 agonists in vitro in the three subsets and assessed the intracellular production of IL1-alpha (α), IL1-beta (β), IL-6, IL-8, TNF-α, and IL-10 of elderly adults (median 83 [67-90] years old;n= 20) compared with young controls (median 35 [27-40] years old;n= 20). Ex vivo, the elderly adults showed a higher percentage of classical monocytes that expressed intracellular IL1-α (p= .001), IL1-β (p= .001), IL-6 (p= .002), and IL-8 (p= .007). Similar results were obtained both for the intermediate and nonclassical subsets and in vitro. Polyfunctionality was higher in the elderly adults. The functionality ex vivo was strongly associated with soluble inflammatory markers. The activation phenotype was independently associated with the anti-cytomegalovirus IgG levels and with functional and cognitive decline. These data demonstrate that monocytes are key cell candidates for the source of the high soluble inflammatory levels. Our findings suggest that cytomegalovirus infection might be a driving force in the activation of monocytes and is associated with the functional and cognitive decline.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Antigens, CD
- Case-Control Studies
- Cognition Disorders
- Cytomegalovirus Infections
- Female
- Humans
- Immunoglobulin G
- Interleukins
- Male
- Monocytes
- Phenotype
- Tumor Necrosis Factor-alpha
Keywords
- Aging
- CMV
- Cognitive
- Inflammation
- Mini-mental
- Monocyte function
Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by unresolved inflammation and tissue repair pathologies triggered by repeated organic dust exposure. The aim of the study was to investigate changes in levels of the cathelicidin related antimicrobial peptide (CRAMP), laminin (LAM-A1), selected Toll-like receptors (TLR) and chemokines in experimental HP in mice. Three and 18-month-old female C57BL/6J mice underwent inhalations of the saline extract of Pantoea agglomerans cells, Gram-negative bacterium common in organic dust and known for its pathogenic impact. The inhalations were repeated daily (28 days). ELISA was used for measuring in lung tissue homogenates concentration of CRAMP, LAM-A1, TLR2, TLR4, TLR8, CXCL9 (chemokine [C-X-C motif] ligand) and CXCL10. Levels of TLR2, TLR4 and CXCL9 were significantly higher in both young and old mice lungs already after 7 days of inhalations, while significant increase of LAM-A1 and CXCL10 was noted after 28 days, compared to untreated samples. TLR8 level was significantly augmented only in young mice. Only CRAMP level significantly declined. Significantly higher TLR8 and CXCL9 concentration in untreated samples were noted in old animals compared to young ones. Significant alterations of the examined factors levels indicate their role in HP pathogenesis.
MeSH Terms
- Administration, Inhalation
- Aerosols
- Aging
- Alveolitis, Extrinsic Allergic
- Animals
- Antimicrobial Cationic Peptides
- Cathelicidins
- Cell Extracts
- Chemokine CXCL10
- Chemokine CXCL9
- Disease Models, Animal
- Female
- Laminin
- Mice
- Mice, Inbred C57BL
- Pantoea
- Protein Precursors
- Toll-Like Receptors
Keywords
- Antimicrobial peptide
- Hypersensitivity pneumonitis
- Mice model
- Modèle murin
- Pantoea agglomerans
- Peptides antimicrobiens
- Pneumopathie d’hypersensibilité
- Récepteurs de type Toll
- Toll-like receptors
Though the pathogenesis of postoperative cognitive dysfunction (POCD) remains unclear, evidence is accumulating for a pivotal role of neuroinflammation in the disease process. Advanced age and severe surgical trauma are two main risk factors for POCD. Lithium, a neuroprotective agent, can alleviate peripheral surgery-induced memory impairment in aged rats. The results of in vivo and in vitro experiments also showed that toll like receptor 4 (TLR4) was associated with the occurrence and development of neuroinflammation and POCD. So we hypothesized that inhibition of TLR4 signaling in the hippocampus maybe involved in the protective effects of prophylactic lithium on the occurrence of inflammation and POCD. In the present study, we incubated BV-2 microglia with 1μg/ml lipopolysaccharide (LPS) to mimic neuroinflammation in vitro. We found that pretreatment with 10mM of lithium or 100nM of TLR4 siRNA could inhibit the tumor necrosis factor (TNF)-α and TLR4 mRNA expression induced by LPS in BV-2 microglia. Furthermore, combination of prophylactic lithium and TLR4 siRNA even decreased their mRNA expression to the baseline levels, which showed that TLR4 signaling may be vital in protective effects of prophylactic lithium on neuroinflammation. So we further undergone the in vivo experiment. Then, we firstly demonstrated that prophylactic 2mM/kg of lithium alleviated splenectomy-induced cognitive impairments, decreased splenectomy-associated systemic, central, and hippocampal TNF-α and interleukin (IL)-1β expression and reduced the increase of CD11b( ) area in hippocampal CA1 region caused by the surgery. Then, we also found that splenectomy merely increased hippocampal TLR2 and TLR4 mRNA levels in aged rats. At last, we confirmed that prophylactic lithium reduced the increased levels of hippocampal TLR4/NF-κB induced by splenectomy. Taken together, these results demonstrate that TLR4 signaling inactivation may contribute to the protective effects of prophylactic lithium on the occurrence of POCD by inhibiting systemic inflammation and especially neuroinflammation.
MeSH Terms
- Aging
- Animals
- CD11b Antigen
- Cell Line
- Cognition Disorders
- Disease Models, Animal
- Interleukin-1beta
- Lipopolysaccharides
- Lithium Chloride
- Male
- Mice
- Microglia
- NF-kappa B
- Neuroimmunomodulation
- Nootropic Agents
- RNA, Messenger
- RNA, Small Interfering
- Random Allocation
- Rats, Sprague-Dawley
- Splenectomy
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Tumor Necrosis Factor-alpha
Keywords
- Lipopolysaccharide
- Lithium chloride
- Microglia
- Postoperative cognitive dysfunction
- Splenectomy
- Toll-like receptor 4
Fracture of the hip (HF) is a significant cause of morbidity and mortality in elderly individuals. HF is an acute stress that triggers a state of inflammation which may affect immune responses and physical recovery. Longitudinal study of the impact of HF on the functions of polymorphonuclear neutrophils (PMNs) in elderly subjects. Data were recorded prior to surgery, 6weeks and 6months later. PMN functions were severely impaired shortly after HF (chemotaxis, phagocytosis, superoxide production) but there was a time-related recovery of some PMN functions (chemotaxis, phagocytosis) over time, except in the case of superoxide production. Whereas FcγRII (CD32) expression remained unchanged, FcγRIII (CD16) increased from low values before surgery to levels of controls 6months post-surgery. This was also the case for the C5a complement receptor and CD11b. TLR2 and TLR4 expressions were unchanged. Cytokine and chemokine secretions by stimulated PMN were altered. TNFα and IL-10 secretions were increased following HF but IL-8 secretion was decreased. Impaired PMN functions prior to surgery were related to alterations in PI3K and NF-κB signaling pathways. Recovery of these functions paralleled increased PI3K activity, although superoxide production remained low. Sustained activation of the NF-κB pathway by TNFα has been reported to involve upregulation of IKKβ kinase activity. Activated IKKβ kinase inhibits ERK1/2 and results in concomitant downstream inhibition of NADPH oxidase complex which can account for sustained impaired production of ROS in HF patients. Our data showed that the stress caused by HF negatively affects initial PMN responses shortly after the event and that may negatively influence clinical outcomes such as resolving long-term inflammation and recovery, as well as explaining susceptibility to opportunistic infections.
MeSH Terms
- Aged
- Aged, 80 and over
- Canada
- Case-Control Studies
- Chemotaxis
- Female
- Hip Fractures
- Humans
- Inflammation
- Interleukin-10
- Interleukin-8
- Male
- Neutrophils
- Orthopedic Procedures
- Perioperative Period
- Phagocytosis
- Postoperative Complications
- Prospective Studies
- Receptors, IgG
- Recovery of Function
- Superoxides
- Tumor Necrosis Factor-alpha
Keywords
- Aging
- Chemotaxis
- Hip fracture
- Inflammation
- Neutrophil functions
- Phagocytosis
Dendritic cells (DCs) are the most potent antigen-presenting cells, playing a key role in induction of both innate and adaptive immunity. Immunosenescence refers to age-associated changes in the immune system, which may be associated with susceptibility to infections and their clinical complications. The precise effects of aging on DCs in immunity to infections are not well understood. Among the common pathogenic microorganisms, the fungus Candida albicans is an important pathogen for the development of invasive infections, especially in immunocompromised individuals, as well as during aging. To make a comparative in vitro evaluation of the immunomodulatory function of DCs challenged with C. albicans, by phagocytosis of the fungal cells, and determine the involvement of TLR2 and TLR4 receptors. For this purpose, DCs were generated with the use of peripheral blood monocytes from healthy young and aged subjects. The phagocytosis of C. albicans is developed by DCs in TLR2- and TLR4-dependent way. This mechanism is not affected by aging. Given the important role of the DCs in responses against the fungus, it is evident that if changes in phagocytosis occurred with aging, impairment in the elderly could develop. However, the evidence that phagocytosis of this fungus by DCs is not impaired with aging, brings us to the question of which are the mechanisms truly associated with the prevalence of certain diseases in the elderly.
MeSH Terms
- Adult
- Aged
- Aging
- Candida albicans
- Cells, Cultured
- Dendritic Cells
- Humans
- Immunity
- Middle Aged
- Monocytes
- Phagocytosis
- Toll-Like Receptor 2
- Toll-Like Receptor 4
Keywords
- C. albicans
- Dendritic cell
- Immunosenescence
- Phagocytosis and Toll like-receptors
Short-term fine particles (PM(2.5)) exposure is associated with reduced heart rate variability, a strong predictor of cardiac mortality among older people. Identifying modifiable factors that confer susceptibility is essential for intervention. We evaluated whether Toll-like receptor 2 (TLR2) methylation, a reversible immune-epigenetic process, and its dietary modulation by flavonoids and methyl nutrients, modify susceptibility to heart rate variability effects following PM(2.5) exposure. We measured heart rate variability and PM(2.5) repeatedly over 11 years (1275 total observations) among 573 elderly men from the Normative Aging Study. Blood TLR2 methylation was analyzed using pyrosequencing. Daily flavonoid and methyl nutrients intakes were assessed through the Food Frequency Questionnaire (FFQ). Every 10 μg/m(3) increase in 48-hour PM(2.5) moving average was associated with 7.74% (95% CI: -1.21% to 15.90%; P=0.09), 7.46% (95% CI: 0.99% to 13.50%; P=0.02), 14.18% (95% CI: 1.14% to 25.49%; P=0.03), and 12.94% (95% CI: -2.36% to 25.96%; P=0.09) reductions in root mean square of successive differences, standard deviation of normal-to-normal intervals, low-frequency power, and high-frequency power, respectively. Higher TLR2 methylation exacerbated the root mean square of successive differences, standard deviation of normal-to-normal intervals, low-frequency, and high-frequency reductions associated with heightened PM2.5 (P(interaction)=0.006, 0.03, 0.05, 0.04, respectively). Every interquartile-range increase in flavonoid intake was associated with 5.09% reduction in mean TLR2 methylation (95% CI: 0.12% to 10.06%; P=0.05) and counteracted the effects of PM2.5 on low frequency (P(interaction)=0.05). No significant effect of methyl nutrients on TLR2 methylation was observed. Higher TLR2 methylation may confer susceptibility to adverse cardiac autonomic effects of PM2.5 exposure in older individuals. Higher flavonoid intake may attenuate these effects, possibly by decreasing TLR2 methylation.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Autonomic Nervous System Diseases
- Bradycardia
- Cohort Studies
- Diet
- Epigenomics
- Flavonoids
- Geriatric Assessment
- Heart Conduction System
- Humans
- Immunomodulation
- Male
- Methylation
- Particulate Matter
- Prognosis
- Prospective Studies
- Survival Rate
- Toll-Like Receptor 2
Keywords
- epidemiology
- epigenetics
- heart rate variability
- inflammation
- nutrition
The major forms of inflammatory canine arthritis are immune-mediated arthritis (IMA) and septic arthritis (SA), although some cases of cruciate disease (CD) are associated with significant levels of synovitis. In this study, the bacteria associated with canine arthritis were identified and mRNA expression levels of Toll-like receptors (TLRs) and pro-inflammatory cytokines determined. Of the 40 synovial fluid samples analysed, bacteria were isolated from 12 samples by culture (2 CD, 10 SA) and detected in 4 samples (3 CD, 1 SA) using culture-independent methods. Statistically significant increases in TLR2, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-12 mRNA expression were seen in all disease groups compared to normal controls. All disease groups had decreased mRNA expression of other TLRs compared to normal controls, but this did not reach statistical significance. Synovial fluid cell counts revealed that the highest number and proportion of mononuclear cells and neutrophils were found in the IMA and SA samples, respectively. Age had an effect on the TLR and cytokine mRNA expression profiles: TNF-α (p=0.043) and IL-12 (p=0.025) mRNA expression was increased and TLR4 mRNA expression was reduced (p=0.033) in dogs up to 4 years of age compared to older animals. In the 10 SA samples from which bacteria were isolated, statistically significant increases in TLR2, TLR7, TNF-α and IL-6 mRNA expression were observed. It is concluded that canine arthritis is associated with increased mRNA levels of pro-inflammatory cytokines, which could in some cases be mediated by bacteria through activation of TLR2.
MeSH Terms
- Aging
- Animals
- Arthritis
- Arthritis, Infectious
- Bacteria
- Cytokines
- Dog Diseases
- Dogs
- Genes, Bacterial
- Genes, rRNA
- Inflammation Mediators
- RNA, Messenger
- Synovial Fluid
- Synovitis
- Toll-Like Receptors
- Transcriptome
Keywords
- Arthritis
- Bacteria
- Canine
- Cytokines
- Toll-like receptors
Globoid cell leukodystrophy is a lysosomal storage disease characterized by the loss of galactocerebrosidase. Galactocerebrosidase loss leads to the accumulation of psychosine and subsequent oligodendrocyte cell death, demyelination, macrophage recruitment, and astroglial activation and proliferation. To date, no studies have elucidated the mechanism of glial cell activation and cytokine and chemokine up-regulation and release. We explored a novel explanation for the development of the pathological changes in the early stages of globoid cell leukodystrophy associated with toll-like receptor (TLR) 2 up-regulation in the hindbrain and cerebellum as a response to dying oligodendrocytes. TLR2 up-regulation on microglia/macrophages coincided with morphological changes consistent with activation at 2 and 3 weeks of age. TLR2 up-regulation on activated microglia/macrophages resulted in astrocyte activation and marked up-regulation of cytokines/chemokines. Because oligodendrocyte cell death is an important feature of globoid cell leukodystrophy, we tested the ability of TLR2 reporter cells to respond to oligodendrocyte cell death. These reporter cells responded in vitro to medium conditioned by psychosine-treated oligodendrocytes, indicating the likelihood that oligodendrocytes release a TLR2 ligand during apoptosis. TLRs are a member of the innate immune system and initiate immune and inflammatory events; therefore, the identification of TLR2 as a potential driver in the activation of central nervous system glial activity in globoid cell leukodystrophy may provide important insight into its pathogenesis.
MeSH Terms
- Aging
- Animals
- Astrocytes
- Calcium-Binding Proteins
- Cell Aggregation
- Cell Line
- Cell Shape
- Chemokines
- Disease Models, Animal
- Fluorescence
- Glial Fibrillary Acidic Protein
- Humans
- Immunity, Innate
- Leukodystrophy, Globoid Cell
- Macrophages
- Mice
- Microfilament Proteins
- Microglia
- Myelin Sheath
- Oligodendroglia
- Psychosine
- RNA, Messenger
- Rhombencephalon
- Signal Transduction
- Toll-Like Receptor 1
- Toll-Like Receptor 2
- Up-Regulation
Chronic, low grade inflammation is a characteristic of old age. Innate immune system cells such as dendritic cells (DCs) from the elderly display a pro-inflammatory phenotype associated with increased reactivity to self. Lithium is a well-established anti-inflammatory agent used in the treatment of bipolar disorders. It has also been reported to reduce inflammation in DCs. Here, we investigated whether Lithium is effective in reducing the inflammatory responses in DCs from the elderly. The effect of Lithium Chloride (LiCl) was compared on the response of TLR4 agonist, LPS and TLR2 agonist, PAM3CSK4 stimulated aged and young DCs. LiCl enhanced the production of IL-10 in LPS stimulated young DCs. However, it did not affect TNF-α and IL-6 production. In contrast, in aged DCs, LiCl reduced the secretion of TNF-α and IL-6 in LPS stimulated DCs but did not increase IL-10. LiCl had no significant effect on PAM3CSK4 responses in aged and young DCs. LiCl treated DCs also displayed differences at the level of CD4 T cell priming and polarization. LPS-stimulated young DCs reduced IFN-γ secretion and biased the Th cell response towards Th2/Treg while LiCl treated aged DCs only reduced IFN-γ secretion but did not bias the response towards Th2/Treg. In summary, our data suggests that LiCl reduces inflammation in aged and young DCs via different mechanisms. Furthermore, the effect of LiCl is different on LPS and PAM3CSK4 responses.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- B7-1 Antigen
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Proliferation
- Dendritic Cells
- Humans
- Immunity, Innate
- Inflammation
- Interleukin-10
- Interleukin-6
- Lipopolysaccharides
- Lipoproteins
- Lithium Chloride
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Tumor Necrosis Factor-alpha
- Young Adult
Keywords
- Aging
- Dendritic cells
- Human
- Lithium Chloride
- TLR2
- TLR4
Toll-like receptors (TLRs) are traditionally associated with immune-mediated host defense. Here, we ascribe a novel extra-immune, hypothalamic-associated function to TLR2, a TLR-family member known to recognize lipid components, in the protection against obesity. We found that TLR2-deficient mice exhibited mature-onset obesity and susceptibility to high-fat diet (HFD)-induced weight gain, via modulation of food intake. Age-related obesity was still evident in chimeric mice, carrying comparable TLR2( ) immune cells, suggesting a non-hematopoietic-related involvement of this receptor. TLR2 was up-regulated with age or HFD in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, a brain area participating in central-metabolic regulation, possibly modulating the hypothalamic-anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH). Direct activation of TLR2 in a hypothalamic-neuronal cell-line via its known ligands, further supports its capacity to mediate non-immune related metabolic regulation. Thus, our findings identify TLR2 expressed by hypothalamic neurons as a potential novel regulator of age-related weight gain and energy expenditure.
MeSH Terms
- Aging
- Animals
- Cell Line
- Diet, High-Fat
- Energy Metabolism
- Hypothalamus
- Ligands
- Mice
- Obesity
- Pro-Opiomelanocortin
- Toll-Like Receptor 2
- alpha-MSH
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 mo) and aged (18-20 mo) BALB/c mice. Aged mice exhibit increased bacterial colonization and delayed wound closure over time compared with 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 s.c. injection of KC, aged mice recruited fewer neutrophils at increasing doses of KC compared with 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.
MeSH Terms
- Aging
- Animals
- Chemotaxis, Leukocyte
- Disease Models, Animal
- Down-Regulation
- Mice
- Neutrophil Infiltration
- Neutrophils
- Skin
- Staphylococcal Infections
- Wound Healing