Abstract WP283: Sex Differences in Hipoxic-ischemic Encephalopathy Are Modulated by Cx3cl1/Cx3cr1 Signaling

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Javiera B Bravo-Alegria ◽  
Louise D McCullough ◽  
Fudong Liu
Keyword(s):  
Flow Cytometry ◽  
Sex Differences ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Protective Mechanism ◽  
Sexually Dimorphic ◽  
Beneficial Effects ◽  
Peripheral Leukocytes ◽  
Inhibitory Signaling ◽  
Ischemic Encephalopathy

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of cognitive impairment in children. Clinically, male infants are more sensitive to the ischemic insult and have worse long-term deficits than girls. The mechanism underlying the sex difference remains elusive. Our previous study using an HIE animal model on post-natal day 10 (P10) mice has revealed that male animals exhibited worse outcomes than females, corresponding to an increased microglial activation that initiates post-ischemia immune responses. CX3CL1/CX3CR1 axis is an endogenous inhibitory signaling pathway that keeps microglia quiescent in normal brains. Whether the CX3CL1/CX3CR1 axis is sex-differently expressed in neonatal brains to cause the sexually dimorphic phenotypes of HIE is not known. Hypothesis: We hypothesize that neonatal female brains are protected against HIE due to a more robust CX3CL1/CX3CR1 signaling compared to males and that manipulation of CX3CL1/CX3CR1 axis has sex-specific effects on HIE. Methods: C57BL6 P10 mice (WT) of both sexes were subjected to a 45-min Rice-Vanucci model (RVM) to induce HIE. CX3CR1 expression, microglial activation, and the infiltration of peripheral leukocytes were examined by flow cytometry. CX3CR1 knockout mice were also used to evaluate the effect of genetic deletion of CX3CL1/CX3CR1 signaling. Results: WT females had a better outcome after neonatal HIE. In addition, WT females have significantly higher expression of CX3CR1 on microglia at baseline than males, measured by CX3CR1 MFI with flow cytometry. Importantly, the majority of the CX3CR1 + microglia co-expressed CD206, a marker of anti-inflammatory phenotype for phagocytes. CX3CR1 KO females lost the resistance to ischemic damage as the knockout of CX3CR1 gene led to exacerbate HIE outcomes only in females. Conclusions: The high expression of CX3CR1 primes female brains to resist inflammatory responses to HIE and has beneficial effects, though the protective mechanism is not sufficient in male brains. Sex differences seen in neonatal HIE are at least in part ascribed to the sexually dimorphic CX3CL1/CX3CR1 signaling. Funding: R01: NS093042 and R21: NS091794 to Fudong Liu.

scholarly journals Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

2020 ◽  
Author(s):  
Valerie Joers ◽  
Gunasingh Masilamoni ◽  
Doty Kempf ◽  
Alison R Weiss ◽  
Travis Rotterman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sex Differences ◽  
Microglial Activation ◽  
Motor Deficits ◽  
Sexually Dimorphic ◽  
Motor Symptoms ◽  
Tnf Inhibitor ◽  
Nonmotor Symptoms ◽  
Monkey Model

AbstractInflammation has been linked to the development of nonmotor symptoms in Parkinson’s disease (PD), which greatly impact patients’ quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a “gold standard” model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

Abstract T P324: Sex Differences in Ischemic Outcomes and Inflammatory Responses in Neonatal Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mehwish A Mirza ◽  
Kathryn Bentivegna ◽  
Rodney Ritzel ◽  
Kaitlyn H Hajdarovic ◽  
Louise D McCullough ◽  
...  
Keyword(s):  
Sex Differences ◽  
Inflammatory Response ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Activation Markers ◽  
Male And Female ◽  
Hormone Levels ◽  
Time Points ◽  
Cytokine Analysis

Background and Purpose: Neonatal arterial ischemic stroke (NAIS) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insult and suffer more long-term deficits than female infants though the mechanisms remain elusive. Inflammatory processes are fundamental in the pathophysiology of ischemia as microglial activation initiates the inflammatory response after ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in neonatal brains under normal conditions. How these basal sex differences in microglia affect NAIS remains largely unexplored. This study investigated sex differences in stroke phenotypes and inflammation triggered by NAIS. We hypothesize that ischemia induces sex-specific tissue injury in male and female neonates, which is related to differences in microglial activation and inflammatory responses. Methods: Male and female C57BL6 mice were subjected to 60-minute Rice-Vanucci Modeling at post-natal day 10 (P10) to induce NAIS. Stroke outcomes were measured at 24 hours, 72 hours and 7 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry, immunohistochemistry, and multiplex cytokine analysis. Results: At 24 hours no difference in infarct volumes (total infarct: male vs. female 46.6±7.2% vs. 43.2±9.3%, n=6/gp) and in Iba-1 staining of the ischemic brain were seen between male and female neonates. However, at 72 hours female neonates exhibited significantly smaller infarct size and improved behavior outcomes compared to males (total infarct: male vs. female 43.1±9.9% vs. 27.1±8.8%, n=6/gp, p <.05). Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at 72 hours. This male-specific phenotype was also seen at 7 days after injury. There was no difference in hormone levels at any of the three time points after stroke. Conclusions: Acute ischemia leads to an equivalent primary brain injury in male and female P10 mice. However, infarct damage worsens in males at sub-acute time points vs. females, as does the immune response. This sex difference independent of hormone levels exists in NAIS.

scholarly journals Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity

2016 ◽  
Vol 311 (2) ◽  
pp. R211-R216 ◽  
Author(s):  
C. Griffin ◽  
N. Lanzetta ◽  
L. Eter ◽  
K. Singer
Keyword(s):  
Sex Differences ◽  
Animal Studies ◽  
Inflammatory Responses ◽  
Disease Risk ◽  
Reproductive Age ◽  
Sexually Dimorphic ◽  
Metabolic Dysfunction ◽  
Diet Induced Obesity ◽  
Dietary Obesity ◽  
Males And Females

It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses.

scholarly journals Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy

2015 ◽  
Vol 12 (1) ◽  
pp. 32 ◽  
Author(s):  
Mehwish A Mirza ◽  
Rodney Ritzel ◽  
Yan Xu ◽  
Louise D McCullough ◽  
Fudong Liu
Keyword(s):  
Inflammatory Responses ◽  
Hypoxic Ischemic Encephalopathy ◽  
Sexually Dimorphic ◽  
Ischemic Encephalopathy

scholarly journals Investigating the reliability and sex differences of digit lengths, ratios, and hand measures in infants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luisa Ernsten ◽  
Lisa M. Körner ◽  
Martin Heil ◽  
Gareth Richards ◽  
Nora K. Schaal
Keyword(s):  
Sex Differences ◽  
Measurement Techniques ◽  
Directional Asymmetry ◽  
Computer Assisted ◽  
Sexually Dimorphic ◽  
Digit Ratios ◽  
Androgen Exposure ◽  
Prenatal Androgen Exposure ◽  
Test Retest Reliability ◽  
Prenatal Androgen

AbstractHands and digits tend to be sexually dimorphic and may reflect prenatal androgen exposure. In the past years, the literature introduced several hand and digit measures, but there is a lack of studies in prepubertal cohorts. The available literature reports more heterogeneous findings in prepubertal compared to postpubertal cohorts. The comparability of the available studies is further limited by the study design and different measurement techniques. The present study compared the reliability and sex differences of available hand and digit measures, namely digit lengths of 2D, 3D, 4D, 5D, digit ratios 2D:4D, 2D:5D, 3D:4D, 3D:5D, 4D:5D, relative digit lengths rel2, rel3, rel4, rel5, directional asymmetry of right and left 2D:4D (Dr-l), hand width, length, and index of 399 male and 364 female 6-month-old German infants within one study using only indirect and computer-assisted measurements. The inter-examiner reliability was excellent while the test-retest reliability of hand scans was only moderate to high. Boys exhibited longer digits as well as wider and longer hands than girls, but smaller digit ratios, with ratios comprising the fifth digit revealing the largest effect sizes. Other hand and digit ratios revealed sex differences to some extent. The findings promote the assumption of sexual dimorphic hand and digit measures. However, by comparing the results of the available literature, there remains an uncertainty regarding the underlying hypothesis. Specifically in prepubertal cohorts, i.e. before the influence of fluctuating hormones, significant effects should be expected. It seems like other factors than the influence of prenatal androgens contribute to the sexual dimorphism in hand and digit lengths.

scholarly journals Synergistic attenuation of ovariectomy-induced bone loss by combined use of fish oil and 17β-oestradiol

2017 ◽  
Vol 117 (4) ◽  
pp. 479-489 ◽  
Author(s):  
Youri Jin ◽  
Myoungsook Lee ◽  
Yongsoon Park
Keyword(s):  
Transcription Factor ◽  
Bone Loss ◽  
Protective Efficacy ◽  
Recovery Period ◽  
Serum Levels ◽  
Protective Mechanism ◽  
Beneficial Effects ◽  
Combined Use ◽  
Related Transcription Factor ◽  
Turnover Markers

AbstractOestrogen and n-3 PUFA, especially EPA and DHA, have been reported to have beneficial effects on bone loss. Thus, the purpose of the present study was to investigate the synergistic bone-protective mechanism of combined treatments of EPA+DHA supplementation and oestrogen injection in ovariectomised rats. Rats were fed a modified American Institute of Nutrition-93G diet with 0 %, 1 % or 2 % n-3 PUFA (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and after a 1-week recovery period rats were injected with either 17β-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Combined use of n-3 PUFA and E2 synergistically increased femoral cortical bone volume, bone mineral content and the bone expression of runt-related transcription factor 2 (RUNX2), but decreased the bone expression of IL-1β. Both n-3 PUFA and E2 decreased the bone expressions of IL-7, TNF-α and PPAR-γ, and increased the bone expression of oestrogen receptor-α. n-3 PUFA in the presence of E2 and E2 alone significantly decreased the bone expressions of IL-1β and IL-6 and increased the bone expression of RUNX2. E2 significantly decreased the serum levels of bone turnover markers and the bone expression of receptor activator of NF-κB ligand, but decreased the bone expression of osteoprotegerin. The combined use of n-3 PUFA and E2 exerted synergistic bone-protective efficacy through up-regulation of RUNX2, an essential transcription factor for bone formation, as well as the suppression of bone-resorbing cytokine IL-1β.

Sex differences in melanotic encapsulation responses (immunocompetence) in the damselfly Lestes forcipatus Rambur

2002 ◽  
Vol 80 (9) ◽  
pp. 1578-1583 ◽  
Author(s):  
Christopher P Yourth ◽  
Mark R Forbes ◽  
Robert L Baker
Keyword(s):  
Sex Differences ◽  
Immune Responses ◽  
Life Histories ◽  
Mass Gain ◽  
Sexually Dimorphic ◽  
Foreign Objects ◽  
Males And Females ◽  
And Gender ◽  
Parasitic Mites ◽  
Melanotic Encapsulation

A few studies have shown that male and female invertebrates differ in immunity and that these differences appear related to differences in sexual dimorphism and gender differences in life histories. Melanotic encapsulation of foreign objects in insects is one form of immunity. The damselfly Lestes forcipatus Rambur is moderately sexually dimorphic, and much is known about patterns of mass gain in congeners relating to differences in life history between males and females. In this study, females were more immunoresponsive than males under controlled temperatures, following emergence, and at a time when parasitic mites were challenging these hosts. However, males and females that overlapped in mass at emergence did not differ in their immune responses. Males in better condition at emergence were more immunoresponsive than lighter males, but this relation was not found in females. Sex differences in immune expression may have implications for how females versus males are able to deal with challenges from parasites, under varying environmental conditions.

Abstract T P238: Microglial CX3CR1 Required for M2 Polarization and Recovery After Intracerebral Hemorrhage

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Roslyn A Taylor ◽  
Matthew D Hammond ◽  
Youxi Ai ◽  
Lauren H Sansing
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Intracerebral Hemorrhage ◽  
Gait Analysis ◽  
Functional Outcome ◽  
Cylinder Test ◽  
M2 Microglia ◽  
Inflammatory Phenotype ◽  
Peripheral Leukocytes ◽  
The Right

Introduction: Intracerebral hemorrhage (ICH) results in the activation of microglia, the resident immune cells of the central nervous system. Microglia may polarize into an M1, pro-inflammatory phenotype, or an M2 phenotype associated with repair. CX3CR1 is a chemokine receptor on microglia and monocyte subsets. CX3CR1-null microglia have been shown to have dysregulated inflammation. We hypothesize that CX3CR1-null microglia have a prolonged M1 phenotype, contributing to worse functional outcome after ICH. Methods: ICH was modeled by injection of 20μl of blood into the right striatum. Neurological deficit was quantified using digital gait analysis, cylinder test, and beam walking. Mice were sacrificed 14 days after ICH; brains were harvested for flow cytometry and immunohistochemistry (IHC). C57BL/6 (WT) and CX3CR1 GFP/GFP (CX3CR1-null) mice were irradiated and reconstituted with bone marrow from WT mice carrying the congenic marker CD45.1 to generate bone marrow chimeras (CD45.1WT or CD45.1CX3CR1-null). M1 microglia were identified as expressing MHCII and M2 microglia with CD206. Results: The CD45.1CX3CR1-null mice show worse functional outcome 14 days after ICH by cylinder test (p=0.002), beam walking (p=<0.001) and gait analysis (p=0.02). By flow cytometry, few peripheral leukocytes remain in the brain at 14 days, indicating that F4/80 + and CD11b + cells visualized by IHC are likely microglia, not peripheral macrophages. By IHC, CD45.1 CX3CR1-null mice have significantly more amoeboid F4/80 + MHCII + cells per field (M1 microglia) than CD45.1WT mice (p=0.02). CD45.1 CX3CR1-null mice have significantly fewer CD11b + CD206 + cells per field (M2 microglia) compared to CD45.1WT mice (p=0.04). Conclusions: Our results suggest microglial CX3CR1 signaling is necessary for microglia to transition from M1 to M2 and contribute to recovery after ICH.

scholarly journals Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3322 ◽  
Author(s):  
Xuguang Li ◽  
Tianyi Yuan ◽  
Di Chen ◽  
Yucai Chen ◽  
Shuchan Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Inflammatory Responses ◽  
Therapeutic Option ◽  
Crystal Form ◽  
Human Coronary Artery ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Cardioprotective Effects

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

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