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

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.

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Repair and recovery mechanisms following critical illness

10.1093/med/9780199600830.003.0309 ◽

2016 ◽

Author(s):

Geoffrey Bellingan ◽

Brijesh V. Patel

Keyword(s):

Critical Illness ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Tissue Injury ◽

Structure And Function ◽

Tissue Structure ◽

Inflammatory Activation ◽

Recovery Mechanisms ◽

And Function

Inflammation is the beneficial host response to foreign challenge or tissue injury that ultimately leads to the restoration of tissue structure and function. Critical illness is associated with an overwhelming and prolonged inflammatory activation. Resolution of the inflammatory response is an active process that requires removal of the inciting stimuli, cessation of the pro-inflammatory response, a timely coordinated removal of tissue leukocyte infiltration, a conversion from ‘toxic’ to reparative tissue environment, and restoration of normal tissue structure and function. Mortality may result from deficits in these resolution mechanisms. Improved delivery of critical care through prevention of harm and removal of stimuli has already delivered significant mortality benefits. Most critically-ill patients present with uncontrolled inflammation, hence anti-inflammatory strategies ameliorating this response are likely to be too late and thus futile. Rather, strategies augmenting endogenous pathways involved in the control and appropriate curtailment of such inflammatory responses may promote resolution, repair, and catabasis. Recent evidence showing that inflammation does not simply ‘fizzle out’, but its resolution involves an active and coordinated series of events. Dysfunction of these resolution checkpoints alters the normal inflammatory pathway, and is implicated in the induction and maintenance of states such as ARDS and sepsis. Improved understanding of resolution biology should provide translational pathways to not only improve survival, but also to prevent long-term morbidity resulting from tissue damage.

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Inflammation: a role for NR4A orphan nuclear receptors?

Biochemical Society Transactions ◽

10.1042/bst0390688 ◽

2011 ◽

Vol 39 (2) ◽

pp. 688-693 ◽

Cited By ~ 109

Author(s):

Jason P. McMorrow ◽

Evelyn P. Murphy

Keyword(s):

Inflammatory Response ◽

Nuclear Receptors ◽

Acute Phase ◽

Immune Cells ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Tissue Injury ◽

Chronic Phase ◽

Psoriatic Skin ◽

Orphan Nuclear Receptors

Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders.

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Isorhynchophylline Ameliorates Cerebral Ischemia/Reperfusion Injury by Inhibiting CX3CR1-Mediated Microglial Activation and Neuroinflammation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.574793 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuanyuan Deng ◽

Ruirong Tan ◽

Fei Li ◽

Yuangui Liu ◽

Jingshan Shi ◽

...

Keyword(s):

Inflammatory Response ◽

Microglial Activation ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Underlying Mechanism ◽

Reperfusion Therapy ◽

Artery Occlusion ◽

Cerebral Ischemic

Reperfusion therapy is an effective way to rescue cerebral ischemic injury, but this therapy also shows the detrimental risk of devastating disorders and death due to the possible inflammatory responses involved in the pathologies. Hence, the therapy of ischemia/reperfusion (I/R) injury is a great challenge currently. Isorhynchophylline (IRN), a tetracyclic oxindole alkaloid extracted from Uncaria rhynchophylla, has previously shown neuroprotective and anti-inflammatory effects in microglial cells. This study systematically investigates the effect of IRN on I/R injury and its underlying mechanism. The effects of IRN on neuronal injury and microglia-mediated inflammatory response were assessed on a rat model with middle cerebral artery occlusion (MCAO) and reperfusion-induced injury. We found that IRN treatment attenuated the infarct volume and improved the neurological function in I/R injury rats. IRN treatment also reduced the neuronal death rate, brain water content, and aquaporin-4 expression in the ischemic penumbra of I/R injury rats’ brains. Besides, IRN treatment could inhibit the following process, including IκB-α degradation, NF-κB p65 activation, and CX3CR1 expression, as well as the microglial activation and inflammatory response. These findings suggest that IRN is a promising candidate to treat the cerebral I/R injury via inhibiting microglia activation and neuroinflammation.

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Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish

Cardiovascular Research ◽

10.1093/cvr/cvz221 ◽

2019 ◽

Vol 116 (7) ◽

pp. 1357-1371 ◽

Cited By ~ 10

Author(s):

Laura Bevan ◽

Zhi Wei Lim ◽

Byrappa Venkatesh ◽

Paul R Riley ◽

Paul Martin ◽

...

Keyword(s):

Inflammatory Response ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Tissue Injury ◽

Cardiac Injury ◽

Repair Process ◽

Adult Zebrafish ◽

Cardiac Damage ◽

Scar Resolution ◽

Macrophage Subsets

Abstract Aims A robust inflammatory response to tissue injury is a necessary part of the repair process but the deposition of scar tissue is a direct downstream consequence of this response in many tissues including the heart. Adult zebrafish not only possess the capacity to regenerate lost cardiomyocytes but also to remodel and resolve an extracellular scar within tissues such as the heart, but this scar resolution process remains poorly understood. This study aims to characterize the scarring and inflammatory responses to cardiac damage in adult zebrafish in full and investigate the role of different inflammatory subsets specifically in scarring and scar removal. Methods and results Using stable transgenic lines, whole organ imaging and genetic and pharmacological interventions, we demonstrate that multiple inflammatory cell lineages respond to cardiac injury in adult zebrafish. In particular, macrophage subsets (tnfα+ and tnfα−) play prominent roles with manipulation of different phenotypes suggesting that pro-inflammatory (tnfα+) macrophages promote scar deposition following cardiac injury whereas tnfα− macrophages facilitate scar removal during regeneration. Detailed analysis of these specific macrophage subsets reveals crucial roles for Csf1ra in promoting pro-inflammatory macrophage-mediated scar deposition. Additionally, the multifunctional cytokine Osteopontin (Opn) (spp1) is important for initial scar deposition but also for resolution of the inflammatory response and in late-stage ventricular collagen remodelling. Conclusions This study demonstrates the importance of a correctly balanced inflammatory response to facilitate scar deposition during repair but also to allow subsequent scar resolution, and full cardiac regeneration, to occur. We have identified Opn as having both pro-fibrotic but also potentially pro-regenerative roles in the adult zebrafish heart, driving Collagen deposition but also controlling inflammatory cell resolution.

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Physical exercise as a human model of limited inflammatory response

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-040 ◽

1998 ◽

Vol 76 (5) ◽

pp. 589-597 ◽

Cited By ~ 53

Author(s):

Pang N Shek ◽

Roy J Shephard

Keyword(s):

Physical Exercise ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Tissue Injury ◽

Active Phase ◽

Human Model ◽

Inflammatory Factors ◽

Trauma Patients ◽

Inflammatory Reactions ◽

Underlying Mechanisms

An inflammatory response represents a fundamental series of humoral and cellular reaction cascades in response to infection, tissue injury, and related insults. An excessive response is commonly seen under the pathological conditions of trauma, sepsis, and burns. It is becoming increasingly evident that most, if not all, of the distinguishing features of a classical inflammatory response are detectable in an exercising individual, namely mobilization and activation of granulocytes, lymphocytes, and monocytes; release of inflammatory factors and soluble mediators; involvement of active phase reactants; and activation of the complement and other reactive humoral cascade systems. While the manifestation of many exercise-induced immune and related changes has been reported and confirmed repeatedly, the underlying mechanisms triggering and modulating the elicited immune responses are, at best, poorly understood. Unlike the exaggerated and sometimes uncontrollable inflammatory response in septic and trauma patients resulting in morbidity and mortality, strenuous and severe exercise normally elicits an inflammatory response of a subclinical nature to facilitate the repairing process for site-specific tissue damage. Regardless of the inciting event, for example trauma, infection, or exercise, and given an appropriate triggering signal, a remarkably similar sequence of inflammatory reactions can be reproduced in the affected host. Therefore, physical exercise and training represent an acceptable and good model for the study of limited inflammatory responses in humans.Key words: trauma, infection, exercise, inflammatory response, cytokines.

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Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms21041279 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1279

Author(s):

Marianne K.O. Grant ◽

Ibrahim Y. Abdelgawad ◽

Christine A. Lewis ◽

Beshay N. Zordoky

Keyword(s):

Sex Differences ◽

Cytochrome P450 ◽

Sexual Dimorphism ◽

Inflammatory Response ◽

Systemic Inflammation ◽

Dependent Manner ◽

Male And Female ◽

Female Mice ◽

Organ Toxicity ◽

Hepatic Cytochrome

Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. In addition to its multi-organ toxicity, DOX treatment has been shown to induce systemic inflammation in patients and experimental animals. Inflammation alters the expression of hepatic cytochrome P450 (CYP) enzymes, which play important roles in drug metabolism and DOX-induced toxicity. Significant sex differences have been reported in DOX-induced toxicity; however, sex differences in DOX-induced systemic inflammation and the potential effects on hepatic CYP expression have not been determined. In the current work, male and female C57Bl/6 mice were administered DOX (20 mg/kg by intraperitoneal injection), and groups of mice were sacrificed 24 and 72 h after DOX administration. DOX elicited a systemic inflammatory response in both male and female mice, but the inflammatory response was stronger in male mice. DOX altered the expression of hepatic CYP isoforms in a sex-dependent manner. Most notably, inhibition of Cyp2c29 and Cyp2e1 was stronger in male than in female mice, which paralleled the sex differences in systemic inflammation. Therefore, sex differences in DOX-induced systemic inflammation may lead to sexually dimorphic drug interactions, in addition to contributing to the previously reported sexual dimorphism in specific DOX-induced organ toxicity.

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Resolvin D1 and Resolvin D2 Protect Against Hypoxia/Reoxygenation Induced Lung and Kidney Damage in a Sickle Cell Mouse Model of Acute Vaso-Occlusive Crisis

Blood ◽

10.1182/blood.v126.23.966.966 ◽

2015 ◽

Vol 126 (23) ◽

pp. 966-966

Author(s):

Alessandro Mattè ◽

Antonio Recchiuti ◽

Charles Serhan ◽

Angela Siciliano ◽

Enrica Federti ◽

...

Keyword(s):

Sickle Cell ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Conflicts Of Interest ◽

Tissue Injury ◽

Hexaenoic Acid ◽

Glomerular Sclerosis ◽

Inflammatory Cell Infiltrate ◽

Activation Markers ◽

Hypoxia Reoxygenation

Abstract Sickle cell disease (SCD) is characterized by hemolytic anemia in association with acute and chronic life-threatening clinical complications. Acute vaso-occlusive crisis (VOCs) are the main cause of hospitalization for SCD patients. In VOCs, amplified inflammatory response plays a key role in acute organ damage. Pro-Resolving lipid mediators such as resolvins (Rv) accelerate resolution of acute inflammation in different models, indicating that stimulation of endogenous resolution of inflammatory processes may be an additional strategy in limiting tissue damage. Recent data suggest beneficial effects of Rvs in hypoxia/reoxygenation (H/R) related tissue injury. Here, we study the effects of Rvs on a model of acute VOCs using humanized SCD mice (Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow). We treated SCD and control healthy mice (AA, Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) (n =6-7 animals in each group) with RvD1, 7S, 8R, 17S- trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexaenoic acid, 17R- RvD1, 7S, 8R, 17R- trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexaenoic acid; RvD2, 7S, 16R, 17S-trihydroxy-docosa-4Z, 8E, 10Z, 12E, 14E, 19Z-hexaenoic acid. Mice were treated with RvD1 and RvD2 at the dose of 2.5 ug/Kg by gavage 1 hour (hr) before H/R stress (10 hrs 8% oxygen followed by 3 hrs reoxygenation), which we have used in the past to mimic acute VOCs. We found that RvD1 and RvD2 significantly reduced the H/R-induced (i) increase in neutrophil count; (ii) lung inflammatory cell infiltrate, mucus and thrombi formation; (iii) glomerular inflammatory cell infiltration, glomerular sclerosis and thrombi formation. In the lung of H/R SCD mice, RvD1 prevented the H/R induced up-regulation of (i) cytokines such as MCP2, IL-6 and ET-1; (ii) vascular endothelial activation markers (VCAM-1 and ICAM-1; (iii) cytoprotective systems such as Prx6 and HO-1. In the kidney of H/R SCD mice, RvD1 significantly reduced H/R induced expression of IL-6 and ET-1 as well as HO-1. Our data indicate that RvD1 and RvD2 modulating inflammatory responses related to H/R in SCD, protect sickle cell target organs, and foster resolution. Thus, RvD1 and RvD2 might represent a novel therapeutic approach for acute VOCs in SCD. Disclosures No relevant conflicts of interest to declare.

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

Stroke ◽

10.1161/str.48.suppl_1.wp283 ◽

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.

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Sex differences in the pro-inflammatory cytokine response to endotoxin unfold in vivo but not ex vivo in healthy humans

Innate Immunity ◽

10.1177/1753425917707026 ◽

2017 ◽

Vol 23 (5) ◽

pp. 432-439 ◽

Cited By ~ 14

Author(s):

Alexander Wegner ◽

Sven Benson ◽

Laura Rebernik ◽

Ingo Spreitzer ◽

Marcus Jäger ◽

...

Keyword(s):

Sex Differences ◽

Inflammatory Response ◽

Plasma Cortisol ◽

Cytokine Production ◽

Inflammatory Responses ◽

Ex Vivo ◽

Negative Feedback Regulation ◽

Healthy Humans ◽

Tnf Α

Clinical data indicate that inflammatory responses differ across sexes, but the mechanisms remain elusive. Herein, we assessed in vivo and ex vivo cytokine responses to bacterial endotoxin in healthy men and women to elucidate the role of systemic and cellular factors underlying sex differences in inflammatory responses. Participants received an i.v. injection of low-dose endotoxin (0.4 ng/kg body mass), and plasma TNF-α and IL-6 responses were analyzed over a period of 6 h. In parallel, ex vivo cytokine production was measured in endotoxin-stimulated blood samples obtained immediately before in vivo endotoxin administration. As glucocorticoids (GCs) play an important role in the negative feedback regulation of the inflammatory response, we additionally analyzed plasma cortisol concentrations and ex vivo GC sensitivity of cytokine production. Results revealed greater in vivo pro-inflammatory responses in women compared with men, with significantly higher increases in plasma TNF-α and IL-6 concentrations. In addition, the endotoxin-induced rise in plasma cortisol was more pronounced in women. In contrast, no sex differences in ex vivo cytokine production and GC sensitivity were observed. Together, these findings demonstrate major differences in in vivo and ex vivo responses to endotoxin and underscore the importance of systemic factors underlying sex differences in the inflammatory response.

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Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

Mediators of Inflammation ◽

10.1155/2017/5048616 ◽

2017 ◽

Vol 2017 ◽

pp. 1-23 ◽

Cited By ~ 73

Author(s):

Lila Carniglia ◽

Delia Ramírez ◽

Daniela Durand ◽

Julieta Saba ◽

Juan Turati ◽

...

Keyword(s):

Chronic Pain ◽

Inflammatory Response ◽

Neurodegenerative Diseases ◽

Glial Cells ◽

Inflammatory Mediators ◽

Tissue Damage ◽

Pain Sensitivity ◽

Microglial Activation ◽

Inflammatory Responses ◽

Immune Surveillance

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

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