scholarly journals Transcriptomic Analysis of the Effects of Chemokine Receptor CXCR3 Deficiency on Immune Responses in the Mouse Brain during Toxoplasma gondii Infection

2021 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Kousuke Umeda ◽  
Youta Goto ◽  
Kenichi Watanabe ◽  
Nanako Ushio ◽  
Ragab M. Fereig ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mouse Brain ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Expression Patterns ◽  
Parasite Burden ◽  
Cxc Chemokine ◽  
Immune Related Genes ◽  
The Brain

The obligate intracellular parasite Toxoplasma gondii infects warm-blooded animals, including humans. We previously revealed through a whole-brain transcriptome analysis that infection with T. gondii in mice causes immune response-associated genes to be upregulated, for instance, chemokines and chemokine receptors such as CXC chemokine receptor 3 (CXCR3) and its ligand CXC chemokine ligand 10 (CXCL10). Here, we describe the effect of CXCR3 on responses against T. gondii infection in the mouse brain. In vivo assays using CXCR3-deficient mice showed that the absence of CXCR3 delayed the normal recovery of body weight and increased the brain parasite burden, suggesting that CXCR3 plays a role in the control of pathology in the brain, the site where chronic infection occurs. Therefore, to further analyze the function of CXCR3 in the brain, we profiled the gene expression patterns of primary astrocytes and microglia by RNA sequencing and subsequent analyses. CXCR3 deficiency impaired the normal upregulation of immune-related genes during T. gondii infection, in astrocytes and microglia alike. Collectively, our results suggest that the immune-related genes upregulated by CXCR3 perform a particular role in controlling pathology when the host is chronically infected with T. gondii in the brain.

scholarly journals Astrocytes promote a protective immune response to brain Toxoplasma gondii infection via IL-33-ST2 signaling

2020 ◽  
Vol 16 (10) ◽  
pp. e1009027
Author(s):  
Katherine M. Still ◽  
Samantha J. Batista ◽  
Carleigh A. O’Brien ◽  
Oyebola O. Oyesola ◽  
Simon P. Früh ◽  
...  
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Toxoplasma Gondii ◽  
Brain Tissue ◽  
Immune Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Parasite Burden ◽  
The Brain

It is of great interest to understand how invading pathogens are sensed within the brain, a tissue with unique challenges to mounting an immune response. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts, and initiates robust immune cell recruitment, but little is known about pattern recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but, like many other pattern recognition pathways, IL-33 can signal peripherally, and the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released locally into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment and/or maintenance of blood-derived anti-parasitic immune cells, including proliferating, IFN-γ-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33 receptor-deficient astrocytes fail to mount an adequate adaptive immune response in the CNS to control parasite burden–demonstrating, genetically, that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released locally, and sensed locally, to engage the peripheral immune system in controlling a pathogen.

scholarly journals Astrocytes promote a protective immune response to brain Toxoplasma gondii infection via IL-33-ST2 signaling

2018 ◽  
Author(s):  
Katherine M. Still ◽  
Samantha J. Batista ◽  
Carleigh O’Brien ◽  
Oyebola O. Oyesola ◽  
Simon P. Früh ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Brain Tissue ◽  
Immune Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Parasite Burden ◽  
Beneficial Effects ◽  
The Brain

SUMMARYUnderstanding how invading pathogens are sensed within the brain is necessary to uncover how effective immune response are mounted in immunoprivileged sites. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts and initiates robust immune cell recruitment, but little is known about innate recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment of peripheral anti-parasitic immune cells, including IFN-γ-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33R-deficient astrocytes fail to promote an adaptive immune response in the CNS and control parasite burden, demonstrating that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released and sensed locally, to engage the peripheral immune system in controlling a neurotropic pathogen.

Cannabinoid effects on adenylate cyclase and phosphodiesterase activities of mouse brain

1977 ◽  
Vol 55 (4) ◽  
pp. 934-942 ◽  
Author(s):  
Thomas W. Dolby ◽  
Lewis J. Kleinsmith
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Mouse Brain ◽  
Biogenic Amine ◽  
Specific Activity ◽  
Intraperitoneal Administration ◽  
The Brain

The experiments presented in this paper examine the mechanisms underlying the ability of cannabinoids to alter the in vivo levels of cyclic adenosine 3′,5′-monophosphate (cyclic AMP) in mouse brain. It was found that changes in cyclic AMP levels are a composite result of direct actions of cannabinoids on adenylate cyclase (EC 4.6.1.1) activity and indirect actions involving the potentiation or inhibition of biogenic amine induced activity of adenylate cyclase. Furthermore, the long-term intraperitoneal administration of 1-(−)-Δ-tetrahydrocannabinol to mice produced a form of phosphodiesterase (EC 3.1.4.17) in the brain whose activity is not stimulated by Ca2+, although its basal specific activity is similar to that of control animals. In vitro, the presence of the cannabinoids caused no significant changes in activity of brain PDE at the concentrations tested. Some correlations are presented which imply that many of the observed behavioral and physiological actions of the cannabinoids in mammalian organisms may be mediated via cyclic AMP mechanisms.

scholarly journals Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5–Positive Cd4 Cells and Germinal Centers

1999 ◽  
Vol 190 (8) ◽  
pp. 1115-1122 ◽  
Author(s):  
Lucy S.K. Walker ◽  
Adam Gulbranson-Judge ◽  
Sarah Flynn ◽  
Thomas Brocker ◽  
Chandra Raykundalia ◽  
...  
Keyword(s):  
T Cells ◽  
Fusion Protein ◽  
Chemokine Receptor ◽  
Germinal Center ◽  
Cd4 T Cells ◽  
Germinal Centers ◽  
Interleukin 4 ◽  
Cxc Chemokine ◽  
Germinal Center Formation

Mice rendered deficient in CD28 signaling by the soluble competitor, cytotoxic T lymphocyte–associated molecule 4–immunoglobulin G1 fusion protein (CTLA4-Ig), fail to upregulate OX40 expression in vivo or form germinal centers after immunization. This is associated with impaired interleukin 4 production and a lack of CXC chemokine receptor (CXCR)5 on CD4 T cells, a chemokine receptor linked with migration into B follicles. Germinal center formation is restored in CTLA4-Ig transgenic mice by coinjection of an agonistic monoclonal antibody to CD28, but this is substantially inhibited if OX40 interactions are interrupted by simultaneous injection of an OX40-Ig fusion protein. These data suggest that CD28-dependent OX40 ligation of CD4 T cells at the time of priming is linked with upregulation of CXCR5 expression, and migration of T cells into B cell areas to support germinal center formation.

scholarly journals Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1379-1386 ◽  
Author(s):  
Seyoum Ayehunie ◽  
Eduardo A. Garcia-Zepeda ◽  
James A. Hoxie ◽  
Richard Horuk ◽  
Thomas S. Kupper ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Monocyte Chemoattractant Protein 1 ◽  
Rna Transcripts ◽  
Inflammatory Protein ◽  
Immunodeficiency Virus ◽  
Cxc Chemokine ◽  
Cc Chemokines

Abstract Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.

scholarly journals Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1160-1167 ◽  
Author(s):  
G. Angus McQuibban ◽  
Jiang-Hong Gong ◽  
Julie P. Wong ◽  
John L. Wallace ◽  
Ian Clark-Lewis ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Leukemic Cell ◽  
Proteolytic Processing ◽  
Cc Chemokine ◽  
Monocyte Chemoattractant ◽  
The Matrix

Monocyte chemoattractant protein (MCP)–3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)–MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)–2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.

scholarly journals Differential Expression of the Carbonic Anhydrase Genes for CA VII (Car7) And CA-RP VIII (Car8) in Mouse Brain

1997 ◽  
Vol 45 (5) ◽  
pp. 657-662 ◽  
Author(s):  
Maha M. Lakkis ◽  
K. Sue O'Shea ◽  
Richard E. Tashian
Keyword(s):  
Carbonic Anhydrase ◽  
Mouse Brain ◽  
Expression Patterns ◽  
Granular Cell ◽  
Cortical Layer ◽  
Cell Layers ◽  
High Level ◽  
The Brain ◽  
Lower Expression

The spatial expression patterns of the two α-carbonic anhydrase genes, CA VII and CA-RP VIII (called Car7 and Car8 in the mouse) were examined in the mouse brain by in situ hybridization. These two genes are the most highly conserved evolutionarily among the mammalian α-CAs. Both genes showed a similarly wide expression pattern in the brain. In the cerebrum, mRNA expression was detected in the pia, choroid plexus, and neurons of the cortical layer, thalamus, and medial habenulae. A high level of expression appeared in the pyramidal and granular cells of the hippocampus. In the cerebellum, both Car7 and Car8 were transcribed to different degrees in the Purkinje cells, and a lower expression level occured in the molecular and granular cell layers. Transcription signals for both genes were excluded from the white matter regions.

scholarly journals The leukotriene B4receptor functions as a novel type of coreceptor mediating entry of primary HIV-1 isolates into CD4-positive cells

1998 ◽  
Vol 95 (16) ◽  
pp. 9530-9534 ◽  
Author(s):  
Christer Owman ◽  
Alfredo Garzino-Demo ◽  
Fiorenza Cocchi ◽  
Mikulas Popovic ◽  
Alan Sabirsh ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Viral Entry ◽  
Chemokine Receptors ◽  
Structural Similarity ◽  
Target Cells ◽  
Natural Ligand ◽  
Hiv 1 ◽  
Entry Efficiency ◽  
Receptor Family

The recently cloned human chemoattractant receptor-like (CMKRL)1, which is expressedin vivoin CD4-positive immune cells, has structural homology with the two chemokine receptors C-C chemokine receptor (CCR)5 and C-X-C chemokine receptor (CXCR)4, which serve as the major coreceptors necessary for fusion of the HIV-1 envelope with target cells. In view of the structural similarity, CMKRL1 was tested for its possible function as another HIV-1 coreceptor after stable expression in murine fibroblasts bearing the human CD4 receptor. The cells were infected with 10 primary clinical isolates of HIV-1, and entry was monitored by semiquantitative PCR of viral DNA. The efficiency of the entry was compared with the entry taking place in CD4-positive cells expressing either CCR5 or CXCR4. Seven of the isolates used CMKRL1 for viral entry; they were mainly of the syncytium-inducing phenotype and also used CXCR4. Entry efficiency was higher with CMKRL1 than with CXCR4 for more than half of these isolates. Three of the ten isolates did not use CMKRL1; instead, entry was mediated by both CCR5 and CXCR4. The experiments thus indicate that CMKRL1 functions as a coreceptor for the entry of HIV-1 into CD4-positive cells. In the course of this study, leukotriene B4was shown to be the natural ligand for this receptor (now designated BLTR), which therefore represents a novel type of HIV-1 coreceptor along with the previously identified chemokine receptors. BLTR belongs to the same general chemoattractant receptor family as the chemokine receptors but is structurally more distant from them than are any of the previously described HIV-1 coreceptors.

Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils

2007 ◽  
Vol 293 (2) ◽  
pp. C696-C704 ◽  
Author(s):  
Jia Sun ◽  
Raina Devi Ramnath ◽  
Madhav Bhatia
Keyword(s):  
Substance P ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Binding Activity ◽  
Receptor Expression ◽  
Chemokine Production ◽  
Chemokine Receptor Expression ◽  
Cc Chemokine ◽  
Primary Mouse ◽  
Cxc Chemokine

Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 μM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1α/CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-κB dependent. SP time dependently induced NF-κB p65 binding activity, IκBα degradation, and NF-κB p65 nuclear translocation in neutrophils. Inhibition of NF-κB activation with its inhibitor Bay11-7082 (10 μM) abolished SP-induced NF-κB binding activity and upregulation of MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-κB activation.

Monitoring of Blood Flow by Drug Stimulation on Mouse Brain Using Non-Invasive Photoacoustic Imaging Technology

2007 ◽  
Vol 364-366 ◽  
pp. 1123-1127
Author(s):  
Shi Hua Yang ◽  
Ye Qi Lao
Keyword(s):  
Blood Flow ◽  
Mouse Brain ◽  
Light Absorption ◽  
Brain Function ◽  
Photoacoustic Imaging ◽  
Non Invasive ◽  
Mouse Cerebral Cortex ◽  
Flow Changes ◽  
The Brain

The highlight of photoacosutic imaging (PAI) is a method that combines ultrasonic resolution with high contrast due to light absorption. Photoacoustic signals carry the information of the light absorption distribution of biological tissue, which is often related to its character of structure, physiological and pathological changes because of different physiology conditions in response to different light absorption coefficients. A non-invasive PAI system was developed and successfully acquired in vivo images of mouse brain. Based on the intrinsic PA signals from the brain, the vascular network and the detailed structures of the mouse cerebral cortex were clearly visualized. The ability of PAI monitoring of cerebral hemodynamics was also demonstrated by mapping of the mouse superficial cortex with and without drug stimulation. The extracted PA signals intensity profiles obviously testified that the cerebral blood flow (CBF) in the mouse brain was changed under the stimulation of acetazolamide (ACZ). The experimental results suggest that PAI can provide non-invasive images of blood flow changes, and has the potential for brain function detection.

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