TLR1
Toll-like receptor 1 precursor (EC 3.2.2.6) (Toll/interleukin-1 receptor-like protein) (TIL) (CD281 antigen) [KIAA0012]
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The purpose of this investigation was to evaluate the effects of aging and lifelong exercise on skeletal muscle components of the innate immune system. Additionally, the effects of an acute resistance exercise (RE) challenge were explored. Three groups of men were studied: young exercisers (YE: [i]n[/i] = 10, 25 ± 1 yr; V̇o : 53 ± 3 mL/kg/min; quadriceps size: 78 ± 3 cm ), lifelong aerobic exercisers with a 53 ± 1 yr training history (LLE; [i]n[/i] = 21, 74 ± 1 yr; V̇o : 34 ± 1 mL/kg/min; quadriceps size: 67 ± 2 cm ), and old healthy nonexercisers (OH: [i]n[/i] = 10, 75 ± 1 yr; V̇o : 22 ± 1 mL/kg/min, quadriceps size: 56 ± 3 cm ). Vastus lateralis muscle biopsies were obtained in the basal state and 4 h after RE (3 × 10 reps, 70% of 1 repetition maximum) to assess Toll-like receptors (TLR)1-10, TLR adaptors (Myd88 and TRIF), and NF-κB pathway components (IκΒα and IKKβ) mRNA expression. Basal TLR3, TLR6, and TLR7 tended to be higher ([i]P[/i] ≤ 0.10) with aging (LLE and OH combined). In general, RE increased expression of TLR1 and TLR8 ([i]P[/i] ≤ 0.10) and TLR3 and TLR4 ([i]P[/i] < 0.05), although TLR3 did not respond in OH. Both TLR adaptors also responded to the exercise bout; these were primarily (Myd88, main effect [i]P[/i] ≤ 0.10) or exclusively (TRIF, [i]P[/i] < 0.05) driven by the OH group. In summary, aging appears to increase basal expression of some innate immune components in human skeletal muscle, and lifelong aerobic exercise does not affect this age-related increase. An exercise challenge stimulates the expression of several TLRs, while the TLR adaptor response appears to be dysregulated with aging and maintained with lifelong exercise. Partially preserved muscle mass, coupled with a notable immunity profile, suggests lifelong exercisers are likely better prepared for a stress that challenges the immune system. Findings from this investigation provide novel insight into the effect of aging and lifelong aerobic exercise on structural components of the innate immune system in skeletal muscle of humans. Data presented here suggest aging increases basal expression of select Toll-like receptors (TLRs), and lifelong exercise does not impact this age-related increase. Additionally, acute exercise stimulates gene expression of several TLRs, while the adaptor response is likely dysregulated with aging and maintained with lifelong exercise.
Keywords
- TLR
- aging
- innate immunity
- lifelong exercise
- skeletal muscle
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
Post-viral pneumococcal pneumonia is a leading morbidity and mortality in older patients (≥65years of age). The goal of our current study is to understand the impact of chronological aging on innate immune responses to a secondary, post viral infection with Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using aged murine models of infection, our findings demonstrate increased morbidity and mortality in aged mice within 48h post-secondary S. pneumoniae infection. Increased susceptibility of aged mice was associated with decreased TLR1, TLR6, and TLR9 mRNA expression and diminished IL1β mRNA expression. Examination of NLRP3 inflammasome expression illustrated decreased NLRP3 mRNA expression and decreased IL1β production in aged lung in response to secondary S. pneumoniae infection.
MeSH Terms
- Aging
- Animals
- Disease Models, Animal
- Female
- Host-Pathogen Interactions
- Immunity, Innate
- Inflammasomes
- Interleukin-1beta
- Lung
- Male
- Mice
- Mice, Inbred BALB C
- NLR Family, Pyrin Domain-Containing 3 Protein
- Pneumonia, Pneumococcal
- Streptococcus pneumoniae
- Toll-Like Receptor 1
- Toll-Like Receptor 6
- Toll-Like Receptor 9
The mechanisms of kidney aging are not yet clear. Studies have shown that immunological inflammation is related to kidney aging. Toll-like receptors (TLRs) are one of the receptor types of the body's innate immune system. The function of the TLR system and the mechanisms by which it functions in renal aging remain unclear. In the present study, we, for the first time, systematically investigated the role of the TLR system and the inflammation responses activated by TLRs during kidney aging. We used western blot and immunohistochemistry to systematically analyze the changes in the expression and activation of the endogenous TLR ligands HSP70 and HMGB1, the TLRs (TLR1-TLR11), their downstream signaling pathway molecules MyD88 and Phospho-IRF-3, and the NF-κB signaling pathway molecules Phospho-IKKβ, Phospho-IκBα (NF-κB inhibition factor α), NF-κBp65, and Phospho-NF-κBp65 (activated NF-κB p65) in the kidneys of 3 months old (youth group), 12 months old (middle age group), and 24 months old (elderly group) rats. We used RT-qPCR to detect the mRNA expression changes of the proinflammatory cytokines CCL3, CCL4, CCL5, CD80, TNF-α, and IL-12b in the rat renal tissues of the various age groups. We found that during kidney aging, the HSP70 and HMGB1 expression levels were significantly increased, and the expression levels of TLR1, 2, 3, 4, 5, and 11 and their downstream signaling pathway molecules MyD88 and Phospho-IRF-3 were markedly elevated. Further studies have shown that in the aging kidneys, the expression levels of the NF-κB signaling pathway molecules Phospho-IKKβ, Phospho-IκBα, NF-κBp65, and Phospho-NF-κBp65 were obviously increased, and those of the proinflammatory cytokines CCL3, CCL4, CCL5, CD80, TNF-α, and IL-12b were significantly upregulated. These results showed that the TLR system might play an important role during the kidney aging process maybe by activating the NF-κB signaling pathway and promoting the high expression of inflammation factors.
MeSH Terms
- Aging
- Animals
- Kidney
- Male
- NF-kappa B
- Phosphorylation
- Rats
- Rats, Inbred F344
- Signal Transduction
- Toll-Like Receptors
Aging is associated with a progressive decline in immune function (immunosenescence) resulting in an increased susceptibility to viral and bacterial infections. Here we show reduced expression of Toll-like receptor 1 (TLR1) in polymorphonuclear leukocytes (PMN) and an underlying age-dependent deficiency in PMN bioenergetics. In older (>65 years) adults, stimulation through TLR1 led to lower activation of integrins (CD11b and CD18), lower production of the chemokine IL-8, and lower levels of the phosphorylated signaling intermediate p38 MAP kinase than in PMN from younger donors (21-30 years). In addition, loss of CD62L, a marker of PMN activation, was reduced in PMN of older adults stimulated through multiple pathways. Rescue of PMN from apoptosis by stimulation with TLR1 was reduced in PMN from older adults. In seeking an explanation for effects of aging across multiple pathways, we examined PMN energy utilization and found that glucose uptake after stimulation through TLR1 was dramatically lower in PMN of older adults. Our results demonstrate a reduction in TLR1 expression and TLR1-mediated responses in PMN with aging, and reduced efficiency of bioenergetics in PMN. These changes likely contribute to reduced PMN efficiency in aging through multiple aspects of PMN function and suggest potential therapeutic opportunities.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Energy Metabolism
- Female
- Humans
- Male
- Neutrophils
- Toll-Like Receptor 1
- Young Adult