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1.
Brain Behav Immun ; 115: 652-666, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37992787

RESUMO

Cytokines are potent immunomodulators exerting pleiotropic effects in the central nervous system (CNS). They influence neuronal functions and circuit activities with effects on memory processes and behaviors. Here, we unravel a neuromodulatory activity of interleukin-15 (IL-15) in mouse brain. Acute exposure of hippocampal slices to IL-15 enhances gamma-aminobutyricacid (GABA) release and reduces glutamatergic currents, while chronic treatment with IL-15 increases the frequency of hippocampal miniature inhibitory synaptic transmission and impairs memory formation in the novel object recognition (NOR) test. Moreover, we describe that serotonin is involved in mediating the hippocampal effects of IL-15, because a selective 5-HT3A receptor antagonist prevents the effects on inhibitory neurotransmission and ameliorates mice performance in the NOR test. These findings provide new insights into the modulatory activities of cytokines in the CNS, with implications on behavior.


Assuntos
Interleucina-15 , Memória Episódica , Camundongos , Animais , Interleucina-15/farmacologia , Hipocampo , Transmissão Sináptica/fisiologia , Neurônios
2.
Glia ; 70(1): 89-105, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34487590

RESUMO

Microglia, the brain's resident macrophages, actively contribute to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor-1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice. Our data demonstrate that almost complete microglial depletion increases the duration of NREM sleep and reduces the hippocampal excitatory neurotransmission. The fractalkine receptor CX3CR1 plays a relevant role in these effects, because cx3cr1GFP/GFP mice recapitulate what found in PLX5622-treated mice. Furthermore, during the light phase, microglia express lower levels of cx3cr1 and a reduction of cx3cr1 expression is also observed when cultured microglial cells are stimulated by ATP, a purinergic molecule released during sleep. Our findings suggest that microglia participate in the regulation of sleep, adapting their cx3cr1 expression in response to the light/dark phase, and modulating synaptic activity in a phase-dependent manner.


Assuntos
Microglia , Transmissão Sináptica , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurônios/metabolismo , Sono
3.
Glia ; 70(1): 173-195, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34661306

RESUMO

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1-/- mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.


Assuntos
Microglia , Neurônios , Animais , Encéfalo , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Hipocampo , Camundongos , Compostos Orgânicos/farmacologia , Sinapses/fisiologia
4.
Neurobiol Dis ; 174: 105894, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36240950

RESUMO

Experience-dependent neuronal changes and brain plasticity occur throughout life as animals adapt to their environment. Structural, morphological, and cellular modifications promoted by exposure to environmental enrichment (EE) have been reported to improve neuronal functions, increase hippocampal neurogenesis, ameliorate memory tasks and cognitive performance, and have beneficial effects on several brain diseases, including cancer. We specifically addressed the role of the EE in counteracting neuronal dysfunction in mice bearing glioma in the primary visual cortex. By recording spontaneous and evoked currents with patch clamp techniques in acute slices obtained from standard and enriched-housed mice, we found that the presence of glioma globally reduced the excitatory and inhibitory transmissions in the peritumoral area. The exposure to an enriched environment counteracts the tumor-mediated depression of both excitatory and inhibitory neuronal activities, with a more pronounced impact on evoked transmission. The effect of EE on glioma was also associated with reduced tumor cell proliferation. These results elucidate the impact of EE on excitatory and inhibitory neurotransmission of the primary visual cortex in control and glioma-bearing mice.


Assuntos
Glioma , Córtex Visual Primário , Camundongos , Animais , Meio Ambiente , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia
5.
Brain Behav Immun ; 105: 1-14, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688338

RESUMO

Neuroinflammation is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, peripheral immune cells were discovered as pivotal players that promptly participate in this process, speeding up neurodegeneration during progression of the disease. In particular, infiltrating T cells and natural killer cells release inflammatory cytokines that switch glial cells toward a pro-inflammatory/detrimental phenotype, and directly attack motor neurons with specific ligand-receptor signals. Here, we assessed the presence of lymphocytes in the spinal cord of sporadic ALS patients. Furthermore, we demonstrate that blocking the extravasation of immune cells in the central nervous system using Natalizumab (NAT), an antibody for the α4 integrin, reduces the level of interferon-γ in the spinal cord of ALS mouse models, such as the hSOD1G93A and TDP43A315T mice, modifying microglia and astrocytes phenotype, increasing motor neuron number and prolonging the survival time. Taken together, our results establish a central role for the immune cells as drivers of inflammation in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Neurônios Motores , Doenças Neuroinflamatórias , Medula Espinal , Superóxido Dismutase/genética , Superóxido Dismutase-1
6.
Glia ; 69(11): 2682-2698, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34310727

RESUMO

Many epigenetic modifications occur in glioma, in particular the histone-deacetylase class proteins play a pivotal role in glioma development, driving the proliferation rate and the invasiveness of tumor cells, and modulating the tumor microenvironment. In this study, we evaluated the role of the histone deacetylase HDAC8 in the regulation of the immune response in glioma and tumor growth. We found that inhibition of HDAC8 by the specific inhibitor PCI-34051 reduces tumor volume in glioma mouse models. We reported that HDAC8 modulates the viability and the migration of human and murine glioma cells. Interestingly, HDAC8 inhibition increases the acetylation of alpha-tubulin, suggesting this epigenetic modification controls glioma migration. Furthermore, we identify HDAC8 as a key molecule that supports a poorly immunogenic tumor microenvironment, modulating microglial phenotype and regulating the gene transcription of NKG2D ligands that trigger the Natural Killer cell-mediated cytotoxicity of tumor cells. Altogether, these results identify HDAC8 as a key actor in glioma growth and tumor microenvironment, and pave the way to a better knowledge of the molecular mechanisms of immune escape in glioma.


Assuntos
Glioma , Histona Desacetilases , Intervenção Coronária Percutânea , Animais , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/imunologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Imunidade , Camundongos , Microambiente Tumoral
7.
Brain Behav Immun ; 97: 423-439, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34343616

RESUMO

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal's ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.


Assuntos
Microglia , Receptores de Glucocorticoides , Animais , Feminino , Hipocampo/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Microglia/metabolismo , Neurogênese , Neurônios/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores Imunológicos , Estresse Psicológico
8.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200955

RESUMO

Nanocarriers are delivery platforms of drugs, peptides, nucleic acids and other therapeutic molecules that are indicated for severe human diseases. Gliomas are the most frequent type of brain tumor, with glioblastoma being the most common and malignant type. The current state of glioma treatment requires innovative approaches that will lead to efficient and safe therapies. Advanced nanosystems and stimuli-responsive materials are available and well-studied technologies that may contribute to this effort. The present study deals with the development of functional chimeric nanocarriers composed of a phospholipid and a diblock copolymer, for the incorporation, delivery and pH-responsive release of the antiglioma agent TRAM-34 inside glioblastoma cells. Nanocarrier analysis included light scattering, protein incubation and electron microscopy, and fluorescence anisotropy and thermal analysis techniques were also applied. Biological assays were carried out in order to evaluate the nanocarrier nanotoxicity in vitro and in vivo, as well as to evaluate antiglioma activity. The nanosystems were able to successfully manifest functional properties under pH conditions, and their biocompatibility and cellular internalization were also evident. The chimeric nanoplatforms presented herein have shown promise for biomedical applications so far and should be further studied in terms of their ability to deliver TRAM-34 and other therapeutic molecules to glioblastoma cells.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Lipossomos/administração & dosagem , Nanopartículas/administração & dosagem , Polímeros/química , Pirazóis/administração & dosagem , Apoptose , Proliferação de Células , Glioma/metabolismo , Glioma/patologia , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/química , Nanopartículas/química , Células Tumorais Cultivadas
9.
Brain Behav Immun ; 81: 484-494, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279682

RESUMO

An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1ß, and enhanced the concentration of prostaglandin E2 (PGE2). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE2 levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Inflamação/metabolismo , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Citocinas/imunologia , Citocinas/metabolismo , Dinoprostona/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ibuprofeno/farmacologia , Inflamação/imunologia , Interleucina-1beta/metabolismo , Cinurenina/metabolismo , Lipopolissacarídeos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Plasticidade Neuronal/imunologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
10.
J Neurosci ; 37(14): 3926-3939, 2017 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-28292827

RESUMO

Oleandrin is a glycoside that inhibits the ubiquitous enzyme Na+/K+-ATPase. In addition to its known effects on cardiac muscle, recent in vitro and in vivo evidence highlighted its potential for anticancer properties. Here, we evaluated for the first time the effect of oleandrin on brain tumors. To this aim, mice were transplanted with human or murine glioma and analyzed for tumor progression upon oleandrin treatment. In both systems, oleandrin impaired glioma development, reduced tumor size, and inhibited cell proliferation. We demonstrated that oleandrin does the following: (1) enhances the brain-derived neurotrophic factor (BDNF) level in the brain; (2) reduces both microglia/macrophage infiltration and CD68 immunoreactivity in the tumor mass; (3) decreases astrogliosis in peritumoral area; and (4) reduces glioma cell infiltration in healthy parenchyma. In BDNF-deficient mice (bdnftm1Jae/J) and in glioma cells silenced for TrkB receptor expression, oleandrin was not effective, indicating a crucial role for BDNF in oleandrin's protective and antitumor functions. In addition, we found that oleandrin increases survival of temozolomide-treated mice. These results encourage the development of oleandrin as possible coadjuvant agent in clinical trials of glioma treatment.SIGNIFICANCE STATEMENT In this work, we paved the road for a new therapeutic approach for the treatment of brain tumors, demonstrating the potential of using the cardioactive glycoside oleandrin as a coadjuvant drug to standard chemotherapeutics such as temozolomide. In murine models of glioma, we demonstrated that oleandrin significantly increased mouse survival and reduced tumor growth both directly on tumor cells and indirectly by promoting an antitumor brain microenvironment with a key protective role played by the neurotrophin brain-derived neurotrophic factor.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Cardenolídeos/uso terapêutico , Glicosídeos Cardíacos/uso terapêutico , Glioma/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Animais , Neoplasias Encefálicas/patologia , Cardenolídeos/farmacologia , Glicosídeos Cardíacos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Glioma/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , Carga Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Brain Behav Immun ; 73: 584-595, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29981425

RESUMO

Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the "pro-inflammatory" phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the "pro-inflammatory" phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor γ subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS.


Assuntos
Microglia/fisiologia , Neurônios Motores/fisiologia , Canais de Potássio Cálcio-Ativados/fisiologia , Esclerose Lateral Amiotrófica/patologia , Animais , Morte Celular , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Fenótipo , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Canais de Potássio Cálcio-Ativados/metabolismo , Pirazóis/farmacologia , Medula Espinal/patologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/fisiologia
12.
Brain Behav Immun ; 58: 261-271, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27474084

RESUMO

It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.


Assuntos
Encefalite/metabolismo , Meio Ambiente , Fluoxetina/administração & dosagem , Microglia/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Animais , Citocinas/metabolismo , Depressão , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Estresse Psicológico
13.
Front Immunol ; 14: 1223096, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37564648

RESUMO

In recent years, biomedical research efforts aimed to unravel the mechanisms involved in motor neuron death that occurs in amyotrophic lateral sclerosis (ALS). While the main causes of disease progression were first sought in the motor neurons, more recent studies highlight the gliocentric theory demonstrating the pivotal role of microglia and astrocyte, but also of infiltrating immune cells, in the pathological processes that take place in the central nervous system microenvironment. From this point of view, microglia-astrocytes-lymphocytes crosstalk is fundamental to shape the microenvironment toward a pro-inflammatory one, enhancing neuronal damage. In this review, we dissect the current state-of-the-art knowledge of the microglial dialogue with other cell populations as one of the principal hallmarks of ALS progression. Particularly, we deeply investigate the microglia crosstalk with astrocytes and immune cells reporting in vitro and in vivo studies related to ALS mouse models and human patients. At last, we highlight the current experimental therapeutic approaches that aim to modulate microglial phenotype to revert the microenvironment, thus counteracting ALS progression.


Assuntos
Esclerose Lateral Amiotrófica , Camundongos , Animais , Humanos , Esclerose Lateral Amiotrófica/genética , Microglia/patologia , Astrócitos/patologia , Neurônios Motores/patologia
14.
Cancer Immunol Res ; 11(9): 1280-1295, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37343073

RESUMO

Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of natural killer (NK) cells to the lung. C-C motif chemokine receptor-like 2 (CCRL2) is a nonsignaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27- CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2'-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell-mediated lung immune surveillance.


Assuntos
Neoplasias Pulmonares , Receptores CCR , Humanos , Receptores CCR/genética , Células Endoteliais , Pulmão , Células Matadoras Naturais/metabolismo
15.
Nat Commun ; 14(1): 3103, 2023 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-37248289

RESUMO

The mechanisms of communication between the brain and the immune cells are still largely unclear. Here, we characterize the populations of resident natural killer (NK) cells and innate lymphoid cells (ILC) 1 in the meningeal dura layer of adult mice. We describe that ILC1/NK cell-derived interferon-γ and acetylcholine can contribute to the modulation of brain homeostatic functions, shaping synaptic neuronal transmission and neurotransmitter levels with effects on mice behavior. In detail, the interferon-γ plays a role in the formation of non-spatial memory, tuning the frequency of GABAergic neurotransmission on cortical pyramidal neurons, while the acetylcholine is a mediator involved in the modulation of brain circuitries that regulate anxiety-like behavior. These findings disclose mechanisms of immune-to-brain communication that modulate brain functions under physiological conditions.


Assuntos
Acetilcolina , Interferon gama , Animais , Camundongos , Linfócitos , Imunidade Inata , Células Matadoras Naturais , Ansiedade
16.
Cancers (Basel) ; 14(11)2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35681612

RESUMO

Microglia and lymphocytes are fundamental constituents of the glioblastoma microenvironment. In this review, we summarize the current state-of-the-art knowledge of the microglial role played in promoting the development and aggressive hallmarks of this deadly brain tumor. Particularly, we report in vitro and in vivo studies related to glioblastoma models and human patients to outline the symbiotic bidirectional interaction between microglia, lymphocytes, and tumor cells that develops during tumor progression. Furthermore, we highlight the current experimental therapeutic approaches that aim to shape these interplays, such as adeno-associated virus (AAV) delivery and CAR-T and -NK cell infusion, and to modulate the tumor microenvironment in an anti-tumoral way, thus counteracting glioblastoma growth.

17.
Life (Basel) ; 12(4)2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35455028

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked disease, caused by a mutant dystrophin gene, leading to muscle membrane instability, followed by muscle inflammation, infiltration of pro-inflammatory macrophages and fibrosis. The calcium-activated potassium channel type 3.1 (KCa3.1) plays key roles in controlling both macrophage phenotype and fibroblast proliferation, two critical contributors to muscle damage. In this work, we demonstrate that pharmacological blockade of the channel in the mdx mouse model during the early degenerative phase favors the acquisition of an anti-inflammatory phenotype by tissue macrophages and reduces collagen deposition in muscles, with a concomitant reduction of muscle damage. As already observed with other treatments, no improvement in muscle performance was observed in vivo. In conclusion, this work supports the idea that KCa3.1 channels play a contributing role in controlling damage-causing cells in DMD. A more complete understanding of their function could lead to the identification of novel therapeutic approaches.

18.
Commun Biol ; 5(1): 517, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641653

RESUMO

Gut microorganisms and the products of their metabolism thoroughly affect host brain development, function and behavior. Since alterations of brain plasticity and cognition have been demonstrated upon motor, sensorial and social enrichment of the housing conditions, we hypothesized that gut microbiota and metabolome could be altered by environmental stimuli, providing part of the missing link among environmental signals and brain effects. In this preliminary study, metagenomic and metabolomic analyses of mice housed in different environmental conditions, standard and enriched, identify environment-specific microbial communities and metabolic profiles. We show that mice housed in an enriched environment have distinctive microbiota composition with a reduction in gut bacterial richness and biodiversity and are characterized by a metabolomic fingerprint with the increase of formate and acetate and the decrease of bile salts. We demonstrate that mice treated with a mixture of formate and acetate recapitulate some of the brain plasticity effects modulated by environmental enrichment, such as hippocampal neurogenesis, neurotrophin production, short-term plasticity and cognitive behaviors, that can be further exploited to decipher the mechanisms involved in experience-dependent brain plasticity.


Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Ácidos Graxos Voláteis , Formiatos , Metaboloma , Camundongos
19.
Biomolecules ; 11(12)2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34944418

RESUMO

The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers of the microglia phenotype could find application in a wide range of human diseases, and creates opportunities for the discovery and development of tailored therapeutic interventions. Among these, recent studies highlight the pivotal role of the potassium channels in regulating microglial functions in physiological and pathological conditions such as Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. In this review, we summarize the current knowledge of the involvement of the microglial potassium channels in several neurodegenerative diseases and their role as modulators of microglial homeostasis and dysfunction in CNS disorders.


Assuntos
Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Canais de Potássio/metabolismo , Animais , Biomarcadores/metabolismo , Progressão da Doença , Regulação da Expressão Gênica , Homeostase , Humanos , Microglia/patologia
20.
Front Immunol ; 12: 730128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552593

RESUMO

Several types of cancer grow differently depending on the environmental stimuli they receive. In glioma, exposure to an enriched environment (EE) increases the overall survival rate of tumor-bearing mice, acting on the cells that participate to define the tumor microenvironment. In particular, environmental cues increase the microglial production of interleukin (IL)-15 which promotes a pro-inflammatory (antitumor) phenotype of microglia and the cytotoxic activity of natural killer (NK) cells, counteracting glioma growth, thus representing a virtuous mechanism of interaction between NK cells and microglia. To mimic the effect of EE on glioma, we investigated the potential of creating engineered microglia as the source of IL-15 in glioma. We demonstrated that microglia modified with recombinant adeno-associated virus serotype 2 (rAAV2) carrying IL-15 (rAAV2-IL-15), to force the production of IL-15, are able to increase the NK cells viability in coculture. Furthermore, the intranasal delivery of rAAV2-IL-15 microglia triggered the interplay with NK cells in vivo, enhancing NK cell recruitment and pro-inflammatory microglial phenotype in tumor mass of glioma-bearing mice, and ultimately counteracted tumor growth. This approach has a high potential for clinical translatability, highlighting the therapeutic efficacy of forced IL-15 production in microglia: the delivery of engineered rAAV2-IL-15 microglia to boost the immune response paves the way to design a new perspective therapy for glioma patients.


Assuntos
Neoplasias Encefálicas/terapia , Dependovirus/metabolismo , Terapia Genética , Glioma/terapia , Imunoterapia , Interleucina-15/metabolismo , Microglia/transplante , Microambiente Tumoral , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Citotoxicidade Imunológica , Dependovirus/genética , Dependovirus/imunologia , Engenharia Genética , Glioma/genética , Glioma/imunologia , Glioma/metabolismo , Interleucina-15/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Fenótipo , Transdução Genética , Carga Tumoral
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