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1.
Science ; 379(6627): 84-88, 2023 01 06.
Article in English | MEDLINE | ID: mdl-36603070

ABSTRACT

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport.


Subject(s)
Brain , Subarachnoid Space , Animals , Humans , Mice , Dura Mater/cytology , Dura Mater/physiology , Endothelium/cytology , Endothelium/physiology , Subarachnoid Space/cytology , Subarachnoid Space/physiology , Epithelium/physiology , Brain/anatomy & histology , Brain/immunology , Cerebrospinal Fluid/physiology
2.
Nature ; 612(7940): 417-429, 2022 12.
Article in English | MEDLINE | ID: mdl-36517712

ABSTRACT

The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.


Subject(s)
Brain , Immune System , Neuroimmunomodulation , Brain/immunology , Brain/physiology , Brain/physiopathology , Immune System/immunology , Immune System/physiology , Immune System/physiopathology , Neuroimmunomodulation/immunology , Neuroimmunomodulation/physiology , Spinal Cord/immunology , Spinal Cord/physiology , Spinal Cord/physiopathology , Humans , Nervous System Diseases/immunology , Nervous System Diseases/physiopathology , Nervous System Diseases/psychology
3.
Science ; 378(6619): 485, 2022 11 04.
Article in English | MEDLINE | ID: mdl-36378990
4.
Proc Natl Acad Sci U S A ; 119(37): e2201645119, 2022 09 13.
Article in English | MEDLINE | ID: mdl-36070344

ABSTRACT

Neuroimmune interactions are crucial for regulating immunity and inflammation. Recent studies have revealed that the central nervous system (CNS) senses peripheral inflammation and responds by releasing molecules that limit immune cell activation, thereby promoting tolerance and tissue integrity. However, the extent to which this is a bidirectional process, and whether peripheral immune cells also promote tolerance mechanisms in the CNS remains poorly defined. Here we report that helminth-induced type 2 inflammation promotes monocyte responses in the brain that are required to inhibit excessive microglial activation and host death. Mechanistically, infection-induced monocytes express YM1 that is sufficient to inhibit tumor necrosis factor production from activated microglia. Importantly, neuroprotective monocytes persist in the brain, and infected mice are protected from subsequent lipopolysaccharide-induced neuroinflammation months after infection-induced inflammation has resolved. These studies demonstrate that infiltrating monocytes promote CNS homeostasis in response to inflammation in the periphery and demonstrate that a peripheral infection can alter the immunologic landscape of the host brain.


Subject(s)
Brain , Encephalitis , Homeostasis , Monocytes , Neuroimmunomodulation , Trichinella spiralis , Trichinellosis , Animals , Brain/immunology , Brain/parasitology , Encephalitis/immunology , Encephalitis/parasitology , Homeostasis/immunology , Lectins/metabolism , Mice , Microglia/immunology , Monocytes/immunology , Trichinella spiralis/immunology , Trichinellosis/immunology , Trichinellosis/pathology , beta-N-Acetylhexosaminidases/metabolism
6.
J Virol ; 96(15): e0080422, 2022 08 10.
Article in English | MEDLINE | ID: mdl-35852355

ABSTRACT

CD4dim CD8bright T cells are a mature population of CD8+ T cells that upon activation upregulate CD4 dimly on their surface. Expression of CD4 on these cells suggests that they can be an additional source of HIV neuroinvasion and persistence in the brain. We used HIV-infected NOD/SCID/IL-2rcγ-/- (NSG) humanized mice to track CD4dim CD8bright T cell homing to the brain and define their role in HIV dissemination into the brain. We report here that CD4dim CD8bright T cells are found in the brain at a median frequency of 2.6% and in the spleen at median frequency of 7.6% of CD3+ T cells. In the brain, 10 to 20% of CD4dim CD8bright T cells contain integrated provirus, which is infectious as demonstrated by viral outgrowth assay. CD4dim CD8bright T cells in the brain exhibited significantly higher expression of the brain homing receptors CX3CR1 and CXCR3 in comparison to their single-positive CD8+ T cell counterpart. Blocking lymphocyte trafficking into the brain of humanized mice via anti-VLA4 and anti-LFA1 antibodies reduced CD4dim CD8bright T cell trafficking into the brain by 60% and diminished brain HIV proviral DNA by 72%. Collectively, our findings demonstrate that CD4dim CD8bright T cells can home to the brain and support productive HIV replication. These studies also reveal for the first time that CD4dim CD8bright T cells are capable of HIV neuroinvasion and are a reservoir for HIV. IMPORTANCE We report here a seminal finding of a novel population of T cells, termed CD4dim CD8bright T cells, that plays a role in HIV neuroinvasion and is a reservoir for HIV in the brain.


Subject(s)
Brain , CD4 Antigens , CD8 Antigens , CD8-Positive T-Lymphocytes , Cell Movement , HIV Infections , HIV-1 , Viral Tropism , Animals , Brain/immunology , Brain/metabolism , Brain/virology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CX3C Chemokine Receptor 1/metabolism , HIV Infections/immunology , HIV Infections/virology , HIV-1/pathogenicity , Humans , Interleukin Receptor Common gamma Subunit/deficiency , Mice , Mice, Inbred NOD , Mice, SCID , Proviruses/genetics , Proviruses/isolation & purification , Receptors, CXCR3/metabolism , Receptors, Lymphocyte Homing/metabolism
7.
Immunol Cell Biol ; 100(7): 482-496, 2022 08.
Article in English | MEDLINE | ID: mdl-35706327

ABSTRACT

Previous studies investigating innate leukocyte recruitment into the brain after cerebral ischemia have shown conflicting results. Using distinct cell surface and intracellular markers, the current study evaluated the contributions of innate immune cells to the poststroke brain following 1-h middle cerebral artery occlusion (tMCAO) or permanent MCAO (pMCAO), and assessed whether these cells ascribed to an inflammatory state. Moreover, we examined whether there is evidence for leukocyte infiltration into the contralateral (CL) hemisphere despite the absence of stroke infarct. We observed the recruitment of peripheral neutrophils, monocytes and macrophages into the hemisphere ipsilateral (IL) to the ischemic brain infarct at 24 and 96 h following both tMCAO and pMCAO. In addition, we found evidence of increased leukocyte recruitment to the CL hemisphere but to a lesser extent than the IL hemisphere after stroke. Robust production of intracellular cytokines in the innate immune cell types examined was most evident at 24 h after pMCAO. Specifically, brain-associated neutrophils, monocytes and macrophages demonstrated stroke-induced production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß, while only monocytes and macrophages exhibit a significant expression of arginase 1 (Arg1) after stroke. At 96 h after stroke, brain-resident microglia demonstrated production of TNF-α and IL-1ß following both tMCAO and pMCAO. At this later timepoint, neutrophils displayed TNF-α production and brain-associated macrophages exhibited elevation of IL-1ß and Arg1 after tMCAO. Further, pMCAO induced significant expression of Arg1 and IL-1ß in monocytes and macrophages at 96 h, respectively. These results revealed that brain-associated innate immune cells display various stroke-induced inflammatory states that are dependent on the experimental stroke setting.


Subject(s)
Brain , Immunity, Innate , Inflammation , Ischemic Stroke , Leukocytes , Brain/immunology , Brain/pathology , Brain Ischemia/immunology , Brain Ischemia/pathology , Immunity, Innate/immunology , Inflammation/immunology , Inflammation/pathology , Ischemic Stroke/immunology , Ischemic Stroke/pathology , Leukocytes/immunology , Leukocytes/pathology , Microglia/immunology , Microglia/pathology , Monocytes/immunology , Monocytes/pathology , Stroke/immunology , Stroke/pathology , Tumor Necrosis Factor-alpha/immunology
8.
Proc Natl Acad Sci U S A ; 119(22): e2200230119, 2022 05 31.
Article in English | MEDLINE | ID: mdl-35617432

ABSTRACT

Brain metastases, including prevalent breast-to-brain metastasis (B2BM), represent an urgent unmet medical need in the care of cancer due to a lack of effective therapies. Immune evasion is essential for cancer cells to metastasize to the brain tissue for brain metastasis. However, the intrinsic genetic circuits that enable cancer cells to avoid immune-mediated killing in the brain microenvironment remain poorly understood. Here, we report that a brain-enriched long noncoding RNA (BMOR) expressed in B2BM cells is required for brain metastasis development and is both necessary and sufficient to drive cancer cells to colonize the brain tissue. Mechanistically, BMOR enables cancer cells to evade immune-mediated killing in the brain microenvironment for the development of brain metastasis by binding and inactivating IRF3. In preclinical brain metastasis murine models, locked nucleic acid-BMOR, a designed silencer targeting BMOR, is effective in suppressing the metastatic colonization of cancer cells in the brain for brain metastasis. Taken together, our study reveals a mechanism underlying B2BM immune evasion during cancer cell metastatic colonization of brain tissue for brain metastasis, where B2BM cells evade immune-mediated killing in the brain microenvironment by acquiring a brain-enriched long noncoding RNA genetic feature.


Subject(s)
Brain Neoplasms , Brain , Breast Neoplasms , Immune Evasion , RNA, Long Noncoding , Animals , Brain/immunology , Brain/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Brain Neoplasms/secondary , Breast/pathology , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Immune Evasion/genetics , Mice , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Tumor Microenvironment
9.
Nat Commun ; 13(1): 945, 2022 02 17.
Article in English | MEDLINE | ID: mdl-35177618

ABSTRACT

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target.


Subject(s)
Infarction, Middle Cerebral Artery/complications , Myeloid Cells/immunology , Neuroinflammatory Diseases/immunology , Aged , Aged, 80 and over , Animals , Brain/cytology , Brain/immunology , Brain/pathology , Disease Models, Animal , Female , Gene Knock-In Techniques , Humans , Infarction, Middle Cerebral Artery/immunology , Infarction, Middle Cerebral Artery/pathology , Male , Mice , Microglia/cytology , Microglia/immunology , Middle Aged , Neuroinflammatory Diseases/pathology , Pia Mater/cytology , Pia Mater/immunology , Pia Mater/pathology
10.
Front Immunol ; 13: 835763, 2022.
Article in English | MEDLINE | ID: mdl-35173742

ABSTRACT

A method to stimulate T lymphocytes with a broad range of brain antigens would facilitate identification of the autoantigens for multiple sclerosis and enable definition of the pathogenic mechanisms important for multiple sclerosis. In a previous work, we found that the obvious approach of culturing leukocytes with homogenized brain tissue does not work because the brain homogenate suppresses antigen-specific lymphocyte proliferation. We now report a method that substantially reduces the suppressive activity. We used this non-suppressive brain homogenate to stimulate leukocytes from multiple sclerosis patients and controls. We also stimulated with common viruses for comparison. We measured proliferation, selected the responding CD3+ cells with flow cytometry, and sequenced their transcriptomes for mRNA and T-cell receptor sequences. The mRNA expression suggested that the brain-responding cells from MS patients are potentially pathogenic. The T-cell receptor repertoire of the brain-responding cells was clonal with minimal overlap with virus antigens.


Subject(s)
Brain/immunology , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Multiple Sclerosis/immunology , Receptors, Antigen, T-Cell/genetics , Adolescent , Adult , Autoantigens/immunology , Cell Proliferation , Female , Flow Cytometry , Humans , Lymphocyte Activation , Male , Multiple Sclerosis/blood , Phenotype , Young Adult
11.
Front Immunol ; 12: 819469, 2021.
Article in English | MEDLINE | ID: mdl-35095923

ABSTRACT

In malaria, anti-parasite immune response of the host may lead to dysregulated inflammation causing severe neuropathology arising from extensive damage to the Blood Brain Barrier (BBB). Use of anti-malarial drugs alone can control parasitemia and reduce inflammation but it cannot reduce pathology if chronic inflammation has already set in. In the present study, we have tested the efficacy of a new oral artemsinin based combination therapy (ACT) regimen using a combination of anti-malarial compounds like nanoartemisinin and nanoallylated-chalcone9 [{1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy) phenyl]-prop-2-en-1-one}]given together with anti-inflammatory-cum- anti-malarial compounds like nanoandrographolide and nanocurcumin to C57BL/6 mice infected with P. berghei ANKA. Untreated infected mice developed Experimental Cerebral Malaria (ECM) and died between 10 to 12 days after infection from severe BBB damage. We observed that oral treatments with nanoartemisinin or nano allylated chalcone 9 or nanoandrographolide alone, for 4 days after the onset of ECM, delayed the development of severe neurolopathology but could not prevent it. Nanocurcumin treatment for 4 days on the other hand, prevented damage to the BBB but the mice died because of hyperparasitemia. A single time oral administration of our ACT controlled blood parasitemia and prevented damage to the BBB, but recrudescence occurred due to persistence of parasites in the spleen. However the recrudescent parasites failed to induce ECM and BBB damage, leading to prolonged survival of the animals. A second time treatment at the start of recrudescence led to complete parasite clearance and survival of mice without pathology or parasitemia for 90 days. FACS analysis of spleen cells and gene expression profile in brain and spleen as well as quantitation of serum cytokine by ELISA showed that P. berghei ANKA infection in C57Bl/6 mice leads to a Th1-skewed immune response that result in severe inflammation and early death from ECM. Oral treatment with our ACT prevented a heightened pro-inflammatory response by modulating the Th1, Th2 and Treg immune responses and prevented ECM and death.


Subject(s)
Antimalarials/administration & dosage , Immunologic Factors/administration & dosage , Malaria/drug therapy , Malaria/parasitology , Nanoparticles , Plasmodium berghei/drug effects , Theranostic Nanomedicine , Animals , Blood-Brain Barrier , Brain/drug effects , Brain/immunology , Brain/parasitology , Cytokines/metabolism , Disease Models, Animal , Drug Therapy, Combination , Female , Malaria/immunology , Mice , Spleen/drug effects , Spleen/immunology , Spleen/parasitology
12.
Molecules ; 27(2)2022 Jan 06.
Article in English | MEDLINE | ID: mdl-35056657

ABSTRACT

Inflammaging is a term used to describe the tight relationship between low-grade chronic inflammation and aging that occurs during physiological aging in the absence of evident infection. This condition has been linked to a broad spectrum of age-related disorders in various organs including the brain. Inflammaging represents a highly significant risk factor for the development and progression of age-related conditions, including neurodegenerative diseases which are characterized by the progressive dysfunction and degeneration of neurons in the brain and peripheral nervous system. Curcumin is a widely studied polyphenol isolated from Curcuma longa with a variety of pharmacologic properties. It is well-known for its healing properties and has been extensively used in Asian medicine to treat a variety of illness conditions. The number of studies that suggest beneficial effects of curcumin on brain pathologies and age-related diseases is increasing. Curcumin is able to inhibit the formation of reactive-oxygen species and other pro-inflammatory mediators that are believed to play a pivotal role in many age-related diseases. Curcumin has been recently proposed as a potential useful remedy against neurodegenerative disorders and brain ageing. In light of this, our current review aims to discuss the potential positive effects of Curcumin on the possibility to control inflammaging emphasizing the possible modulation of inflammaging processes in neurodegenerative diseases.


Subject(s)
Aging , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Brain/drug effects , Curcumin/pharmacology , Inflammation/drug therapy , Microglia/drug effects , Neurodegenerative Diseases/drug therapy , Animals , Brain/immunology , Brain/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Microglia/immunology , Microglia/pathology , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/pathology
14.
J Virol ; 96(6): e0131121, 2022 03 23.
Article in English | MEDLINE | ID: mdl-35045263

ABSTRACT

Spread of herpes simplex virus 1 (HSV1) from the periphery to the central nervous system (CNS) can lead to extensive infection and pathological inflammation in the brain, causing herpes simplex encephalitis (HSE). It has been shown that microglia, the CNS-resident macrophages, are involved in early sensing of HSV1 and induction of antiviral responses. In addition, infiltration of peripheral immune cells may contribute to the control of viral infection. In this study, we tested the effect of microglia depletion in a mouse model of HSE. Increased viral titers and increased disease severity were observed in microglia-depleted mice. The effect of microglia depletion was more pronounced in wild-type than in cGas-/- mice, revealing that this immune sensor contributes to the antiviral activity of microglia. Importantly, microglia depletion led to reduced production of type I interferon (IFN), proinflammatory cytokines, and chemokines at early time points after viral entry into the CNS. In line with this, in vitro experiments on murine primary CNS cells demonstrated microglial presence to be essential for IFN RNA induction, and control of HSV1 replication. However, the effect of microglia depletion on the expression of IFNs, and inflammatory cytokines was restricted to the early time point of HSV1 entry into the CNS. There was no major alteration of infiltration of CD45-positive cells in microglia-depleted mice. Collectively, our data demonstrate a key role for microglia in controlling HSV1 replication early after viral entry into the CNS and highlight the importance of a prompt antiviral innate response to reduce the risk of HSE development. IMPORTANCE One of the most devastating and acute neurological conditions is encephalitis, i.e., inflammation of brain tissue. Herpes simplex virus 1 (HSV1) is a highly prevalent pathogen in humans, and the most frequent cause of viral sporadic encephalitis called herpes simplex encephalitis (HSE). HSV1 can infect peripheral neurons and reach the central nervous system (CNS) of humans, where it can be detected by brain resident cells and infiltrating immune cells, leading to protective and damaging immune responses. In this study, we investigated the effects of microglia depletion, the main brain-resident immune cell type. For this purpose, we used a mouse model of HSE. We found that viral levels increased, and disease symptoms worsened in microglia-depleted mice. In addition, mice lacking a major sensor of viral DNA, cGAS, manifested a more pronounced disease than wild-type mice, highlighting the importance of this immune sensor in the activity of microglia. Microglia depletion led to reduced production of many known antiviral factors, most notably type I interferon (IFN). The importance of microglia in the early control of HSV1 spread and the generation of antiviral responses is further demonstrated by experiments on murine mixed glial cell cultures. Interestingly, mice with microglia depletion exhibited an unaltered activation of antiviral responses and recruitment of immune cells from the periphery at later time points of infection, but this did not prevent the development of the disease. Overall, the data highlight the importance of rapid activation of the host defense, with microglia playing a critical role in controlling HSV1 infection, which eventually prevents damage to neurons and brain tissue.


Subject(s)
Encephalitis, Herpes Simplex , Herpesvirus 1, Human , Immunity , Interferon Type I , Microglia , Virus Internalization , Animals , Brain/immunology , Brain/virology , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Encephalitis, Herpes Simplex/immunology , Encephalitis, Herpes Simplex/physiopathology , Herpesvirus 1, Human/metabolism , Immunity/immunology , Inflammation/pathology , Interferon Type I/metabolism , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/virology , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism
15.
Nutrients ; 14(1)2021 Dec 30.
Article in English | MEDLINE | ID: mdl-35011046

ABSTRACT

The composition and activity of the intestinal microbial community structures can be beneficially modulated by nutritional components such as non-digestible oligosaccharides and omega-3 poly-unsaturated fatty acids (n-3 PUFAs). These components affect immune function, brain development and behaviour. We investigated the additive effect of a dietary combination of scGOS:lcFOS and n-3 PUFAs on caecal content microbial community structures and development of the immune system, brain and behaviour from day of birth to early adulthood in healthy mice. Male BALB/cByJ mice received a control or enriched diet with a combination of scGOS:lcFOS (9:1) and 6% tuna oil (n-3 PUFAs) or individually scGOS:lcFOS (9:1) or 6% tuna oil (n-3 PUFAs). Behaviour, caecal content microbiota composition, short-chain fatty acid levels, brain monoamine levels, enterochromaffin cells and immune parameters in the mesenteric lymph nodes (MLN) and spleen were assessed. Caecal content microbial community structures displayed differences between the control and dietary groups, and between the dietary groups. Compared to control diet, the scGOS:lcFOS and combination diets increased caecal saccharolytic fermentation activity. The diets enhanced the number of enterochromaffin cells. The combination diet had no effects on the immune cells. Although the dietary effect on behaviour was limited, serotonin and serotonin metabolite levels in the amygdala were increased in the combination diet group. The combination and individual interventions affected caecal content microbial profiles, but had limited effects on behaviour and the immune system. No apparent additive effect was observed when scGOS:lcFOS and n-3 PUFAs were combined. The results suggest that scGOS:lcFOS and n-3 PUFAs together create a balance-the best of both in a healthy host.


Subject(s)
Brain/drug effects , Brain/immunology , Dietary Supplements , Eating/physiology , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/pharmacology , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/immunology , Immune System/drug effects , Immune System/immunology , Intestines/drug effects , Intestines/immunology , Oligosaccharides/administration & dosage , Oligosaccharides/pharmacology , Animals , Female , Male , Mice, Inbred BALB C , Microbiota/drug effects , Microbiota/immunology , Pregnancy
16.
Cell Death Dis ; 13(1): 33, 2022 01 10.
Article in English | MEDLINE | ID: mdl-35013119

ABSTRACT

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1ß, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.


Subject(s)
Aging/drug effects , Brain/drug effects , Cerebral Hemorrhage/drug therapy , Microglia/drug effects , Neuroinflammatory Diseases/drug therapy , Aging/pathology , Aminopyridines/administration & dosage , Aminopyridines/pharmacology , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , Brain Injuries/drug therapy , Brain Injuries/etiology , Brain Injuries/immunology , Brain Injuries/pathology , Cell Death/drug effects , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/immunology , Cerebral Hemorrhage/pathology , Chemotaxis, Leukocyte/drug effects , Disease Models, Animal , Mice , Microglia/immunology , Microglia/pathology , Neuroinflammatory Diseases/etiology , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/pathology , Pyrroles/administration & dosage , Pyrroles/pharmacology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors
17.
Front Immunol ; 12: 792522, 2021.
Article in English | MEDLINE | ID: mdl-34975893

ABSTRACT

The immune response generated by the body after the incidence of ischemic stroke, runs through the comprehensive process of aftermath. During this process of ischemic stroke, the central neuroinflammation and peripheral immune response seriously affect the prognosis of patients, which has been the focus of research in recent years. As this research scenario progressed, the "dialogue" between central nervous inflammation and peripheral immune response after ischemic stroke has become more closely related. It's worth noting that the spleen, as an important peripheral immune organ, plays a pivotal role in this dialogue. Multiple mechanisms have previously been reported for brain-spleen crosstalk after ischemic stroke. Further, neuroinflammation in the brain can affect the peripheral immune state by activating/inhibiting spleen function. However, the activation of the peripheral immune inflammatory response can work reversibly in the spleen. It further affects intracerebral neuroinflammation through the injured blood-brain barrier. Therefore, paying close attention to the role of spleen as the pivot between central and peripheral immunity in ischemic stroke may help to provide a new target for immune intervention in the treatment of ischemic stroke. In the present review, we reviewed the important role of spleen in central neuroinflammation and peripheral immune response after ischemic stroke. We summarized the relevant studies and reports on spleen as the target of immune intervention which can provide new ideas for the clinical treatment of ischemic stroke.


Subject(s)
Brain/immunology , Ischemic Stroke/immunology , Neuroinflammatory Diseases/immunology , Spleen/immunology , Animals , Anti-Inflammatory Agents/pharmacology , Brain/drug effects , Brain/metabolism , Cytokines/metabolism , Humans , Immunomodulating Agents/pharmacology , Immunotherapy , Inflammation Mediators/metabolism , Ischemic Stroke/metabolism , Ischemic Stroke/therapy , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/therapy , Signal Transduction , Spleen/drug effects , Spleen/metabolism , Stem Cell Transplantation
19.
Food Funct ; 12(19): 9261-9272, 2021 Oct 04.
Article in English | MEDLINE | ID: mdl-34606526

ABSTRACT

Isorhamnetin (ISO), a flavonoid compound isolated from sea-buckthorn (Hippophae rhamnoides L.) fruit, has anti-inflammatory effects. However, the effects of ISO on neuroinflammation and cognitive function are still unclear. The purpose of this study was to evaluate the protective effect of ISO on cognitive impairment in obese mice induced by a high-fat and high fructose diet (HFFD). It has been found that oral administration of ISO (0.03% w/w and 0.06% w/w) for 14 weeks significantly reduced the body weight, food intake, liver weight, liver lipid level, and serum lipid level of HFFD-fed mice. ISO can also significantly prevent HFFD-induced neuronal working, spatial, and long-term memory impairment. Notably, the ISO treatment activated the CREB/BDNF pathway and increased neurotrophic factors in the brains of mice. Furthermore, ISO inhibited HFFD-induced microglial overactivation and down-regulated inflammatory cytokines in both serum and the brain. It can also inhibit the expression of p-JNK, p-p38, and p-NFκB protein in the mouse brain. In conclusion, these results indicated that ISO mitigated HFFD-induced cognitive impairments by inhibiting the MAPK and NFκB signaling pathways, suggesting that ISO might be a plausible nutritional intervention for metabolic syndrome-related cognitive complications.


Subject(s)
Cognitive Dysfunction/prevention & control , Diet, High-Fat/adverse effects , Dietary Sugars/administration & dosage , Dietary Supplements , Neuroinflammatory Diseases/prevention & control , Quercetin/analogs & derivatives , Signal Transduction , Animals , Brain/immunology , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Cognitive Dysfunction/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cytokines/blood , Cytokines/metabolism , Dietary Sugars/adverse effects , Fructose/administration & dosage , MAP Kinase Signaling System , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microglia/physiology , NF-kappa B/metabolism , Neuroinflammatory Diseases/metabolism , Quercetin/administration & dosage , Weight Gain
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