Vimentin regulates chemokine expression and NOD2 activation in brain endothelium during Group B streptococcal infection.

2021 ◽  
Author(s):  
R. Villarreal ◽  
H.S. Manzer ◽  
A.M. Keestra-Gounder ◽  
K.S. Doran
Keyword(s):  
Inflammatory Responses ◽  
Muramyl Dipeptide ◽  
Opportunistic Pathogen ◽  
Invasive Disease ◽  
Brain Endothelium ◽  
Targeted Deletion ◽  
Meningeal Inflammation ◽  
The Central Nervous System ◽  
Group B

Streptococcus agalactiae (Group B Streptococcus , GBS), is an opportunistic pathogen capable of causing invasive disease in susceptible individuals including the newborn. Currently GBS is the leading cause of meningitis in the neonatal period. We have recently shown that GBS interacts directly with host type III intermediate filament vimentin to gain access to the central nervous system. This results in characteristic meningeal inflammation and disease progression; however, the specific role of vimentin in the inflammatory process is unknown. Here we investigate the contribution of vimentin to the pathogenesis of GBS meningitis. We show that a CRISPR targeted deletion of vimentin in human cerebral microvascular endothelial cells (hCMEC) reduced GBS induction of neutrophil attractants IL-8 and CXCL-1, as well as NFκB activation. We further show that inhibition of vimentin localization also prevented similar chemokine activation by GBS. One known chemokine regulator is the nucleotide-binding oligomerization domain containing protein 2 (NOD2), which is known to interact directly with vimentin. Thus, we hypothesized that NOD2 would also promote GBS chemokine induction. We show that GBS infection induced NOD2 transcription in hCMEC comparable to the muramyl dipeptide (MDP) NOD2 agonist, and the chemokine induction was reduced in the presence of a NOD2 inhibitor. Using a mouse model of GBS meningitis we also observed increased NOD2 transcript and NOD2 activation in brain tissue of infected mice. Lastly, we show that NOD2 mediated IL8 and CXCL1 induction required vimentin, further indicating the importance of vimentin in mediating inflammatory responses in brain endothelium.

scholarly journals The Role of Mast Cells in Stroke

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 437 ◽  
Author(s):  
Edoardo Parrella ◽  
Vanessa Porrini ◽  
Marina Benarese ◽  
Marina Pizzi
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Mast Cells ◽  
Brain Edema ◽  
Hemorrhagic Stroke ◽  
Inflammatory Responses ◽  
Adult Brain ◽  
The Central Nervous System

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain–blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators.

Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice

2009 ◽  
Vol 296 (3) ◽  
pp. G685-G695 ◽  
Author(s):  
Stephan C. Bischoff ◽  
Reiner Mailer ◽  
Oliver Pabst ◽  
Gisela Weier ◽  
Wanda Sedlik ◽  
...  
Keyword(s):  
Serotonin Reuptake ◽  
Sulfonic Acid ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Colonic Motility ◽  
Trinitrobenzene Sulfonic Acid ◽  
Targeted Deletion ◽  
Immune Mediated ◽  
Serotonin Reuptake Transporter

Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice.

Arachidonic Acid Derivatives and Neuroinflammation

2021 ◽  
Vol 20 ◽  
Author(s):  
Era Gorica ◽  
Vincenzo Calderone
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Arachidonic Acid ◽  
Prostaglandin E2 ◽  
Phospholipase A2 ◽  
Inflammatory Responses ◽  
The Central Nervous System ◽  
The Brain ◽  
Arachidonic Acid Derivatives

: Neuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset of several neurodegenerative disorders and is considered a typical feature of these disorders. Microglia perform primary immune surveillance and macrophage-like activities within the central nervous system. Activated microglia are predominant players in the central nervous system response to damage related to stroke, trauma, and infection. Moreover, microglial activation per se leads to a proinflammatory response and oxidative stress. During the release of cytokines and chemokines, cyclooxygenases and phospholipase A2 are stimulated. Elevated levels of these compounds play a significant role in immune cell recruitment into the brain. Cyclic phospholipase A2 plays a fundamental role in the production of prostaglandins by releasing arachidonic acid. In turn, arachidonic acid is biotransformed through different routes into several mediators that are endowed with pivotal roles in the regulation of inflammatory processes. Some experimental models of neuroinflammation exhibit an increase in cyclic phospholipase A2, leukotrienes, and prostaglandins such as prostaglandin E2, prostaglandin D2, or prostacyclin. However, findings on the role of the prostacyclin receptors have revealed that their signalling suppresses Th2-mediated inflammatory responses. In addition, other in vitro evidence suggests that prostaglandin E2 may inhibit the production of some inflammatory cytokines, attenuating inflammatory events such as mast cell degranulation or inflammatory leukotriene production. Based on these conflicting experimental data, the role of arachidonic acid derivatives in neuroinflammation remains a challenging issue.

scholarly journals CNS-Spleen Axis – a Close Interplay in Mediating Inflammatory Responses in Burn Patients and a Key to Novel Burn Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Noorisah Khan ◽  
Supreet Kaur ◽  
Carly M. Knuth ◽  
Marc G. Jeschke
Keyword(s):  
Inflammatory Responses ◽  
Immune Dysfunction ◽  
Multiple Organ ◽  
Burn Patients ◽  
Severe Burn ◽  
Therapeutic Techniques ◽  
Immune Balance ◽  
The Central Nervous System ◽  
Immune Imbalance

Severe burn-induced inflammation and subsequent hypermetabolic response can lead to profound infection and sepsis, resulting in multiple organ failure and high mortality risk in patients. This represents an extremely challenging issue for clinicians as sepsis is the leading cause of mortality in burn patients. Since hyperinflammation and immune dysfunction are a result of an immune imbalance, restoring these conditions seem to have promising benefits for burn patients. A key network that modulates the immune balance is the central nervous system (CNS)-spleen axis, which coordinates multiple signaling pathways, including sympathetic and parasympathetic pathways. Modulating inflammation is a key strategy that researchers use to understand neuroimmunomodulation in other hyperinflammatory disease models and modulating the CNS-spleen axis has led to improved clinical outcomes in patients. As the immune balance is paramount for recovery in burn-induced sepsis and patients with hyperinflammatory conditions, it appears that severe burn injuries substantially alter this CNS-spleen axis. Therefore, it is essential to address and discuss the potential therapeutic techniques that target the CNS-spleen axis that aim to restore homeostasis in burn patients. To understand this in detail, we have conducted a systematic review to explore the role of the CNS-spleen axis and its impact on immunomodulation concerning the burn-induced hypermetabolic response and associated sepsis complications. Furthermore, this thorough review explores the role of the spleen, CNS-spleen axis in the ebb and flow phases following a severe burn, how this axis induces metabolic factors and immune dysfunction, and therapeutic techniques and chemical interventions that restore the immune balance via neuroimmunomodulation.

scholarly journals Inflammation Drives Alzheimer's Disease: Emphasis on 5-lipoxygenase pathways

2020 ◽  
Vol 18 ◽  
Author(s):  
Aisha Siddiqui ◽  
Md Sayeed Akhtar ◽  
Zahoor Shah ◽  
Iekhsan Othman ◽  
Yatinesh Kumari
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Inflammatory Responses ◽  
Biologically Active ◽  
Biochemical Pathways ◽  
Physiological Processes ◽  
The Central Nervous System ◽  
Metabolism Enzyme

: It is a known fact that inflammation affects several physiological processes, including the functioning of the central nervous system. Additionally, impairment of lipid mechanisms/pathways have been associated with a number of neurodegenerative disorders and Alzheimer’s Disease (AD) is one of them. However, much attention has been given to the link between tau and beta-amyloid hypothesis in AD pathogenesis/prognosis. Increasing evidences suggest that biologically active lipid molecules could influence the pathophysiology of AD via different mechanism of inflammation. In this review, we intend to highlight the role of inflammatory responses in the context of AD with the emphasis on biochemical pathways of lipid metabolism enzyme, 5-lipoxygenase (5-LO).

scholarly journals The Interleukin-1β/CXCL1/2/Neutrophil Axis Mediates Host Protection against Group B Streptococcal Infection

2014 ◽  
Vol 82 (11) ◽  
pp. 4508-4517 ◽  
Author(s):  
C. Biondo ◽  
G. Mancuso ◽  
A. Midiri ◽  
G. Signorino ◽  
M. Domina ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Group B Streptococcus ◽  
Neutrophil Recruitment ◽  
Interleukin 1Β ◽  
Host Protection ◽  
Target Organs ◽  
Group B ◽  
The Brain ◽  
Deficient Mice

ABSTRACTPrevious studies have indicated that group B streptococcus (GBS), a frequent human pathogen, potently induces the release of interleukin-1β (IL-1β), an important mediator of inflammatory responses. Since little is known about the role of this cytokine in GBS disease, we analyzed the outcome of infection in IL-1β-deficient mice. These animals were markedly sensitive to GBS infection, with most of them dying under challenge conditions that caused no deaths in wild-type control mice. Lethality was due to the inability of the IL-1β-deficient mice to control local GBS replication and dissemination to target organs, such as the brain and the kidneys. Moreover, in a model of inflammation induced by the intraperitoneal injection of killed GBS, a lack of IL-1β was associated with selective impairment in the production of the neutrophil chemokines CXCL1 and CXCL2 and in neutrophil recruitment to the peritoneal cavity. Decreased blood neutrophil counts and impaired neutrophil recruitment to the brain and kidneys were also observed during GBS infection in IL-1β-deficient mice concomitantly with a reduction in CXCL1 and CXCL2 tissue levels. Notably, the hypersusceptibility to GBS infection observed in the immune-deficient animals was recapitulated by neutrophil depletion with anti-Gr1 antibodies. Collectively, our data identify a cytokine circuit that involves IL-1β-induced production of CXCL1 and CXCL2 and leads the recruitment of neutrophils to GBS infection sites. Moreover, our data point to an essential role of these cells in controlling the progression and outcome of GBS disease.

Paradoxical Role of 3-Methyladenine in Pyocyanin-Induced Toxicity in 1321N1 Astrocytoma and SH-SY5Y Neuroblastoma Cells

2013 ◽  
Vol 32 (3) ◽  
pp. 209-218 ◽  
Author(s):  
Amelia J. McFarland ◽  
Gary D. Grant ◽  
Anthony V. Perkins ◽  
Cameron Flegg ◽  
Andrew K. Davey ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Inflammatory Responses ◽  
Neuroblastoma Cells ◽  
Astrocytoma Cells ◽  
The Central Nervous System ◽  
Green Fluorescent ◽  
The Impact ◽  
First Time ◽  
1321N1 Astrocytoma

The role of autophagy in pyocyanin (PCN)-induced toxicity in the central nervous system (CNS) remains unclear, with only evidence from our group identifying it as a mechanism underlying toxicity in 1321N1 astrocytoma cells. Therefore, the aim of this study was to further examine the role of autophagy in PCN-induced toxicity in the CNS. To achieve this, we exposed 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells to PCN (0-100 μmol/L) and tested the contribution of autophagy by measuring the impact of the autophagy inhibitor 3-methyladenine (3-MA) using a series of biochemical and molecular markers. Pretreatment of 1321N1 astrocytoma cells with 3-MA (5 mmol/L) decreased the PCN-induced acidic vesicular organelle and autophagosome formation as measured using acridine orange and green fluorescent protein-LC3 -LC3 fluorescence, respectively. Furthermore, 3-MA (5 mmol/L) significantly protected 1321N1 astrocytoma cells against PCN-induced toxicity. In contrast pretreatment with 3-MA (5 mmol/L) increased PCN-induced toxicity in SH-SY5Y neuroblastoma cells. Given the influence of autophagy in inflammatory responses, we investigated whether the observed effects in this study involved inflammatory mediators. The PCN (100 μmol/L) significantly increased the production of interleukin-8 (IL-8), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) in both cell lines. Consistent with its paradoxical role in modulating PCN-induced toxicity, 3-MA (5 mmol/L) significantly reduced the PCN-induced production of IL-8, PGE2, and LTB4 in 1321N1 astrocytoma cells but augmented their production in SH-SY5Y neuroblastoma cells. In conclusion, we show here for the first time the paradoxical role of autophagy in mediating PCN-induced toxicity in 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells and provide novel evidence that these actions may be mediated by effects on IL-8, PGE2, and LTB4 production.

scholarly journals Recent advances in understanding the molecular basis of group BStreptococcusvirulence

2008 ◽  
Vol 10 ◽  
Author(s):  
Heather C. Maisey ◽  
Kelly S. Doran ◽  
Victor Nizet
Keyword(s):  
Inflammatory Responses ◽  
Molecular Targets ◽  
Invasive Disease ◽  
Valuable Insight ◽  
Complex Interplay ◽  
Group B ◽  
New Research ◽  
Immune Detection ◽  
Insight Into ◽  
Host Tissues

Group BStreptococcuscommonly colonises healthy adults without symptoms, yet under certain circumstances displays the ability to invade host tissues, evade immune detection and cause serious invasive disease. Consequently, Group BStreptococcusremains a leading cause of neonatal pneumonia, sepsis and meningitis. Here we review recent information on the bacterial factors and mechanisms that direct host–pathogen interactions involved in the pathogenesis of Group BStreptococcusinfection. New research on host signalling and inflammatory responses to Group BStreptococcusinfection is summarised. An understanding of the complex interplay between Group BStreptococcusand host provides valuable insight into pathogen evolution and highlights molecular targets for therapeutic intervention.

scholarly journals PPARα Modulation-Based Therapy in Central Nervous System Diseases

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1168
Author(s):  
Deokho Lee ◽  
Yohei Tomita ◽  
William Allen ◽  
Kazuo Tsubota ◽  
Kazuno Negishi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hormone Receptors ◽  
Inflammatory Responses ◽  
Peroxisome Proliferator ◽  
Therapeutic Approaches ◽  
Cns Diseases ◽  
The Central Nervous System ◽  
Peroxisome Proliferator Activated Receptors

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

scholarly journals Role of the inhibitor of serine peptidase 2 (ISP2) of Trypanosoma brucei rhodesiense in parasite virulence and modulation of the inflammatory responses of the host

2021 ◽  
Vol 15 (6) ◽  
pp. e0009526
Author(s):  
David Jessula Levy ◽  
Amy Goundry ◽  
Raquel S. S. Laires ◽  
Tatiana F. R. Costa ◽  
Carlos Mendes Novo ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Inflammatory Responses ◽  
Trypanosoma Brucei Rhodesiense ◽  
Lower Blood ◽  
Tnf Α ◽  
Causative Agents ◽  
The Central Nervous System ◽  
Two Peaks

Trypanosoma brucei rhodesiense is one of the causative agents of Human African Trypanosomiasis (HAT), known as sleeping sickness. The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form T. b. rhodesiense. We generated gene-deficient mutants lacking ISP2 (Δisp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with Δisp2 displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of Δisp2-infected mice had a greater percentage of NOS2+ myeloid cells, IFN-γ+-NK cells and increased TNF-α compared to those infected with WT and parasites re-expressing ISP2 (Δisp2:ISP2). By 13 days the increased NOS2+ population was sustained in Δisp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19+ B lymphocytes, and CD8+ and CD4+ T lymphocytes. Taken together, these findings indicate that ISP2 contributes to T. b. rhodesiense virulence in mice and attenuates the inflammatory response during early infection.

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