Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Kwon, Min Seong; Woo, Seung Kyoon; Kurland, David B.; Yoon, Sung Hwan; Palmer, Andre F.; Banerjee, Uddyalok; Iqbal, Sana; Ivanova, Svetlana; Gerzanich, Volodymyr; Simard, J. Marc

doi:10.3390/ijms16035028

Cited by 99 publications

(76 citation statements)

References 71 publications

(115 reference statements)

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“…Subarachnoid hemorrhage is characterized by sterile inflammation, which is different in some ways from LPS-induced inflammation. In our current study, Hb induced a rapid elevation of pro-inflammatory cytokines, which was similar to the results of LPS stimulation and was consistent with previous in vivo and in vitro studies (Lin et al, 2012;Gram et al, 2013;Kwon et al, 2015). Nevertheless, miR-146a expression was different.…”

Section: Discussionsupporting

confidence: 92%

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

et al. 2020

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Microglial activation and sustained inflammation in the brain can lead to neuronal damage. Hence, limiting microglial activation and brain inflammation is a good therapeutic strategy for inflammatory-associated central nervous disease. MiR-146a is a promising therapeutic microRNA, since it can negatively regulate the inflammatory response. We thus investigated the expression changes of miR-146a after experimental induction of a subarachnoid hemorrhage (SAH) in vivo and in vitro, and we assessed the anti-inflammatory effects of miR-146a in microglial cells in vitro. Primary microglial cells were preincubated with miR-146a before hemoglobin (Hb) treatment. The results indicated that miR-146a decreased gene expression of Hb-induced pro-inflammatory cytokines (TNF-α and IL-1β) and phenotype-related genes (iNOS and CD86) through IRAK1/TRAF6/NF-κB or MAPK signaling pathways, suggesting its pro-resolution activity in microglia. However, contrary to the LPS-induced microglia or macrophage activation model, we did not observe an elevation in miR-146a after activation. Overall, our findings demonstrated that miR-146a was involved in the regulation of brain inflammation and could be considered a novel therapeutic agent for treating brain inflammation.

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Section: Discussionsupporting

confidence: 92%

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

et al. 2020

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“…Statistical comparisons for data measurements were completed using multifactorial analysis of variance (Kwon et al . ) and included a determination for strain effects. Main effects between mouse strains were determined by pooling all WT and BERK‐SS mice into respective groups.…”

Section: Methodsmentioning

confidence: 99%

Effects of living at moderate altitude on pulmonary vascular function and exercise capacity in mice with sickle cell anaemia

Ferguson

Redinius

Yalamanoglu

et al. 2018

The Journal of Physiology

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Exposure to high altitude worsens symptoms and crises in patients with sickle cell disease (SCD). However, it remains unclear whether prolonged exposure to low barometric pressures exacerbates SCD aetiologies or impairs quality of life. We tested the hypothesis that, relative to wild-type (WT) mice, Berkley sickle cell mice (BERK-SS) residing at sea level, mild (1609 m) and moderate (2438 m) altitude would have a higher rate of haemolysis, impaired cardiac function and reduced exercise tolerance, and that the level of altitude would worsen these decrements. Following 3 months of altitude exposure, right ventricular systolic pressure was measured (solid-state transducer). In addition, the adaptive balance between pulmonary vascular endothelial nitric oxide synthase and endothelin was assessed in lung tissue to determine differences in pulmonary vascular adaptation and the speed/duration relationship (critical speed) was used to evaluate treadmill exercise tolerance. At all altitudes, BERK-SS mice had a significantly lower percentage haemocrit and higher total bilirubin and free haemoglobin concentration (P < 0.05 for all). right ventricular systolic pressures in BERK-SS were higher than WT at moderate altitude and also compared to BERK-SS at sea level (P < 0.05, for both). Critical speed was significantly lower in BERK-SS at mild and moderate altitude (P < 0.05). BERK-SS demonstrated exacerbated SCD complications and reduced exercise capacity associated with an increase in altitude. These results suggest that exposure to mild and moderate altitude enhances the progression of SCD in BERK-SS mice compared to healthy WT cohorts and BERK-SS mice at sea level and provides crucial information for the clinical counselling of SCD patients.

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“…It is known that degradation of blood components like heme, fibrinogen and intracellular structures creates damage-associated molecular patterns (DAMPs) that trigger inflammatory signaling cascades [178,179]. One possible inflammatory reaction that is triggered by DAMPs is activation of TLRs that play a key role in the innate immune reaction [180,181]. In a model of IVH, DAMPs led to activation of TLR4 in CP epithelial cells resulting in hypersecretion of CSF.…”

Section: Hemorrhagic Strokementioning

confidence: 99%

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

Solar

Zamani

Kubíčková

et al. 2020

Fluids Barriers CNS

181

142

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The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Cited by 99 publications

References 71 publications

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

Effects of living at moderate altitude on pulmonary vascular function and exercise capacity in mice with sickle cell anaemia

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

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