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Sex-, stress-, and sympathetic post-ganglionic-dependent changes in identity and proportions of immune cells in the dura.

ABSTRACT: Aim of investigation Due to compelling evidence in support of links between sex, stress, sympathetic post-ganglionic innervation, dural immune cells, and migraine, our aim was to characterize the impacts of these factors on the type and proportion of immune cells in the dura. Methods Dural immune cells were obtained from naïve or stressed adult male and female Sprague Dawley rats for flow cytometry. Rats with surgical denervation of sympathetic post-ganglionic neurons of the dura were also studied. Results Immune cells comprise ?17% of all cells in the dura. These included: macrophages/granulocytes ("Macs"; 63.2% of immune cells), dendritic cells (0.88%), T-cells (4.51%), natural killer T-cells (0.51%), natural killer cells (3.08%), and B-cells (20.0%). There were significantly more Macs and fewer B- and natural killer T-cells in the dura of females compared with males. Macs and dendritic cells were significantly increased by stress in males, but not females. In contrast, T-cells were significantly increased in females with a 24-hour delay following stress. Lastly, Macs, dendritic cells, and T-cells were significantly higher in sympathectomized-naïve males, but not females. Conclusions It may not only be possible, but necessary to use different strategies for the most effective treatment of migraine in men and women.

SUBMITTER: McIlvried LA

PROVIDER: S-EPMC5023503 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Sex-, stress-, and sympathetic post-ganglionic-dependent changes in identity and proportions of immune cells in the dura.

McIlvried Lisa A LA Cruz J Agustin JA Borghesi Lisa A LA Gold Michael S MS

Cephalalgia : an international journal of headache 20160711 1

Aim of investigation Due to compelling evidence in support of links between sex, stress, sympathetic post-ganglionic innervation, dural immune cells, and migraine, our aim was to characterize the impacts of these factors on the type and proportion of immune cells in the dura. Methods Dural immune cells were obtained from naïve or stressed adult male and female Sprague Dawley rats for flow cytometry. Rats with surgical denervation of sympathetic post-ganglionic neurons of the dura were also studi ...[more]

PMID: 26970607

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Project description:BackgroundMigraine attacks are associated with sterile inflammation of the dura. Immune cells are a primary source of inflammatory mediators, and we therefore sought to further explore the link between dural immune cells and migraine.ObjectiveBased on the observations that migraine is more common in women than in men, stress is the most common trigger for a migraine attack, and sympathetic post-ganglionic innervation of the dura enables local control of dural immune cells, we hypothesized that stress shifts the balance of inflammatory mediator expression in dural immune cells toward those that trigger a migraine attack, where these changes are larger in females and dependent, at least in part, on sympathetic post-ganglionic innervation of the dura. Our objective was to test this hypothesis.MethodsDura were obtained from naïve or stressed, intact or surgically sympathectomized, adult male and female rats. Dura were assessed immediately or 24 hours after termination of 4 continuous days of unpredictable, mild stressors. Following enzymatic digestion of each dura, myeloid and lymphoid-derived dural immune cells were isolated by fluorescence-activated cell sorting for semi-quantitative polymerase chain reaction analysis.ResultsIn myeloid-derived dural immune cells, there was an increase in pro-inflammatory mediator mRNA following stress, particularly in females, which remained elevated with a 24-hour delay after stress. There was a stress-induced decrease in anti-inflammatory mediator mRNA immediately after stress in females, but not males. The stress-induced changes were attenuated in sympathectomized females. In lymphoid-derived dural immune cells, there was a persistent increase in pro-inflammatory mediator mRNA following stress, particularly in females. A stress-induced increase in anti-inflammatory mediator mRNA was also observed in both males and females, and was further attenuated in sympathectomized females.ConclusionsConsistent with our hypothesis, there is a stress-induced shift in the balance of pro- and anti-inflammatory mediator expression in dural immune cells that is more pronounced in females, and is dependent, at least in part, on sympathetic post-ganglionic innervation in females. This shift in the balance of inflammatory mediator expression may not only play an important role in triggering migraine attacks, but also suggests it may be possible, if not necessary, to employ different strategies to most effectively treat migraine in men and women.

Project description:Cardiac dysautonomia is a common nonmotor symptom of Parkinson's disease (PD) associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies for PD cardiac neurodegeneration are not available, and biomarkers of target engagement are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) recapitulates PD cardiac dysautonomia pathology. We recently used positron emission tomography (PET) to visualize and quantify cardiac sympathetic innervation, oxidative stress, and inflammation in adult male rhesus macaques (Macaca mulatta; n = 10) challenged with 6-OHDA (50mg/kg; i.v.). Twenty-four hours post-intoxication, the animals were blindly and randomly assigned to receive daily doses of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5mg/kg p.o.) or placebo (n = 5). Quantification of PET radioligand uptake showed increased oxidative stress and inflammation one week after 6-OHDA which resolved to baseline levels by twelve weeks, at which time pioglitazone-treated animals showed regionally preserved sympathetic innervation. Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and sex matched normal controls (n = 5). In the heart, 6-OHDA-treated animals showed a significant loss of sympathetic nerve fibers density (tyrosine hydroxylase (TH)-positive fibers). The anatomical distribution of markers of sympathetic innervation (TH) and inflammation (HLA-DR) significantly correlated with respective in vivo PET findings across left ventricle levels and regions. No changes were found in alpha-synuclein immunoreactivity. Additionally, CD36 protein expression was increased at the cardiomyocyte intercalated discs following PPARγ-activation compared to placebo and control groups. Systemic 6-OHDA decreased adrenal medulla expression of catecholamine producing enzymes (TH and aromatic L-amino acid decarboxylase) and circulating levels of norepinephrine, which were attenuated by PPARγ-activation. Overall, these results validate in vivo PET findings of cardiac sympathetic innervation, oxidative stress, and inflammation and illustrate cardiomyocyte CD36 upregulation as a marker of PPARγ target engagement.

Project description:BackgroundBurn patients are prone to infection as well as immunosuppression, which is a significant cause of death. Currently, there is a lack of prognostic biomarkers for immunosuppression in burn patients. This study was conducted to identify immune-related genes that are prognosis biomarkers in post-burn immunosuppression and potential targets for immunotherapy.MethodsWe downloaded the gene expression profiles and clinical data of 213 burn patients and 79 healthy samples from the Gene Expression Omnibus (GEO) database. Immune infiltration analysis was used to identify the proportion of circulating immune cells. Functional enrichment analyses were carried out to identify immune-related genes that were used to build miRNA-mRNA networks to screen key genes. Next, we carried out correlation analysis between immune cells and key genes that were then used to construct logistic regression models in GSE77791 and were validated in GSE19743. Finally, we determined the expression of key genes in burn patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR).ResultsA total of 745 differently expressed genes were screened out: 299 were up-regulated and 446 were down-regulated. The number of Th-cells (CD4+) decreased while neutrophils increased in burn patients. The enrichment analysis showed that down-regulated genes were enriched in the T-cell activation pathway, while up-regulated genes were enriched in neutrophil activation response in burn patients. We screened out key genes (NFATC2, RORA, and CAMK4) that could be regulated by miRNA. The expression of key genes was related to the proportion of Th-cells (CD4+) and survival, and was an excellent predictor of prognosis in burns with an area under the curve (AUC) value of 0.945. Finally, we determined that NFATC2, RORA, and CAMK4 were down-regulated in burn patients.ConclusionWe found that NFATC2, RORA, and CAMK4 were likely prognostic biomarkers in post-burn immunosuppression and potential immunotherapeutic targets to convert Th-cell dysfunction.

Dataset Information

Sex-, stress-, and sympathetic post-ganglionic-dependent changes in identity and proportions of immune cells in the dura.

Publications

Sex-, stress-, and sympathetic post-ganglionic-dependent changes in identity and proportions of immune cells in the dura.

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