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1.
Elife ; 122023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37254842

RESUMO

Resident macrophages are distributed across all tissues and are highly heterogeneous due to adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophages in the sensory ganglia, which have been implicated in different conditions, including neuropathic pain development. However, it is still under debate whether macrophage accumulation in the sensory ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or a result of blood monocyte infiltration. Here, we confirmed that the number of macrophages increased in the sensory ganglia after the spared nerve injury (SNI) model in mice. Using different approaches, we found that the increase in the number of macrophages in the sensory ganglia after SNI is a consequence of the proliferation of resident CX3CR1+ macrophages, which participate in the development of neuropathic pain, but not due to infiltration of peripheral blood monocytes. These proliferating macrophages are the source of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation and neuropathic pain development after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner accounting for neuropathic pain development. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Camundongos , Animais , Traumatismos dos Nervos Periféricos/complicações , Gânglios Espinais , Macrófagos , Gânglios Sensitivos , Células Receptoras Sensoriais , Proliferação de Células , Hiperalgesia
2.
Cell Rep ; 42(4): 112293, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-36952346

RESUMO

Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.


Assuntos
Doenças Desmielinizantes , Remielinização , Animais , Camundongos , Doenças Desmielinizantes/metabolismo , Transcriptoma/genética , Encéfalo/metabolismo , Oligodendroglia/metabolismo , Microglia/metabolismo , Cuprizona/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo
3.
J Clin Invest ; 132(23)2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36227694

RESUMO

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.


Assuntos
Cinurenina , Neuralgia , Animais , Camundongos , Cinurenina/metabolismo , Ácido Quinolínico/metabolismo , Redes e Vias Metabólicas , Células Dendríticas/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
4.
Pain ; 161(8): 1730-1743, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32701834

RESUMO

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Linfócitos T Reguladores , Animais , Hiperalgesia , Camundongos , Camundongos Endogâmicos C57BL , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático , Células Th1
5.
PLoS Pathog ; 15(9): e1007934, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31479495

RESUMO

Mayaro virus (MAYV) is an arbovirus that circulates in Latin America and is emerging as a potential threat to public health. Infected individuals develop Mayaro fever, a severe inflammatory disease characterized by high fever, rash, arthralgia, myalgia and headache. The disease is often associated with a prolonged arthralgia mediated by a chronic inflammation that can last months. Although the immune response against other arboviruses, such as chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), has been extensively studied, little is known about the pathogenesis of MAYV infection. In this study, we established models of MAYV infection in macrophages and in mice and found that MAYV can replicate in bone marrow-derived macrophages and robustly induce expression of inflammasome proteins, such as NLRP3, ASC, AIM2, and Caspase-1 (CASP1). Infection performed in macrophages derived from Nlrp3-/-, Aim2-/-, Asc-/-and Casp1/11-/-mice indicate that the NLRP3, but not AIM2 inflammasome is essential for production of inflammatory cytokines, such as IL-1ß. We also determined that MAYV triggers NLRP3 inflammasome activation by inducing reactive oxygen species (ROS) and potassium efflux. In vivo infections performed in inflammasome-deficient mice indicate that NLRP3 is involved with footpad swelling, inflammation and pain, establishing a role of the NLRP3 inflammasome in the MAYV pathogenesis. Accordingly, we detected higher levels of caspase1-p20, IL-1ß and IL-18 in the serum of MAYV-infected patients as compared to healthy individuals, supporting the participation of the NLRP3-inflammasome during MAYV infection in humans.


Assuntos
Infecções por Alphavirus/imunologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adulto , Idoso , Infecções por Alphavirus/metabolismo , Animais , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Vírus Chikungunya/metabolismo , Vírus da Dengue/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos/imunologia , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espécies Reativas de Oxigênio/metabolismo , Togaviridae/patogenicidade , Zika virus/metabolismo
6.
J Leukoc Biol ; 106(3): 541-551, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31150565

RESUMO

The development of neuropathic pain after peripheral nerve injury involves neuroimmune-glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2-deficient mice. These results suggest that blood-circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2-expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.


Assuntos
Leucócitos/patologia , Traumatismos dos Nervos Periféricos/sangue , Traumatismos dos Nervos Periféricos/patologia , Medula Espinal/patologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Endotélio Vascular/patologia , Feminino , Células-Tronco Hematopoéticas/metabolismo , Hiperalgesia/sangue , Hiperalgesia/complicações , Hiperalgesia/imunologia , Hiperalgesia/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/patologia , Monócitos/patologia , Neuralgia/sangue , Neuralgia/complicações , Neuralgia/imunologia , Neuralgia/patologia , Receptores CCR2/deficiência , Receptores CCR2/metabolismo
7.
Front Immunol ; 10: 3059, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32047492

RESUMO

Neuroimmune-glia interactions have been implicated in the development of neuropathic pain. Interleukin-27 (IL-27) is a cytokine that presents regulatory activity in inflammatory conditions of the central nervous system. Thus, we hypothesized that IL-27 would participate in the neuropathic pain process. Here, we found that neuropathic pain caused by peripheral nerve injury (spared nerve injury model; SNI), was enhanced in IL-27-deficient(-/-) mice, whereas nociceptive pain is similar to that of wild-type mice. SNI induced an increase in the expression of IL-27 and its receptor subunit (Wsx1) in the sensory ganglia and spinal cord. IL-27 receptor was expressed mainly in resident macrophage, microglia, and astrocytes of the sensory ganglia and spinal cord, respectively. Finally, we identify that the antinociceptive effect of IL-27 was not observed in IL-10-/- mice. These results provided evidence that IL-27 is a cytokine produced after peripheral nerve injury that counteracts neuropathic pain development through induction of the antinociceptive cytokine IL-10. In summary, our study unraveled the role of IL-27 as a regulatory cytokine that counteracts the development of neuropathic pain after peripheral nerve damage. In conclusion, they indicate that immunotherapies based on IL-27 could emerge as possible therapeutic approaches for the prevention of neuropathic pain development after peripheral nerve injury.


Assuntos
Suscetibilidade a Doenças , Interleucina-10/metabolismo , Interleucina-27/metabolismo , Neuralgia/etiologia , Neuralgia/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Gânglios Espinais , Interleucina-27/genética , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Traumatismos dos Nervos Periféricos/complicações , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
8.
Pain ; 160(1): 102-116, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30169421

RESUMO

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1ß). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.


Assuntos
Macrófagos/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Transplante de Medula Óssea , Carragenina/toxicidade , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Neuralgia/genética , Neuralgia/cirurgia , Fármacos Neuroprotetores/uso terapêutico , Proteína Adaptadora de Sinalização NOD2/genética , RNA Interferente Pequeno/uso terapêutico , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Xantinas/uso terapêutico
9.
Neurobiol Dis ; 105: 109-116, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28587921

RESUMO

Pathological pain conditions can be triggered after peripheral nerve injury and/or inflammation. It is associated with plasticity of nociceptive pathway in which pain is prolonged even after healing of the injured tissue. Generally combinations of analgesic drugs are not sufficient to achieve selective palliation from chronic pain, besides causing a greater number of side effects. In order to identify novel alternatives for more effective treatments, it is necessary to clarify the underlying mechanisms of pathological pain. It is well established that there are two main components in pathological pain development and maintenance: (i) primary sensory neuron sensitization (peripheral sensitization), and (ii) central sensitization. In both components cytokines and chemokines act as key mediators in pain modulation. CXCL1 is a chemokine that promote both nociceptor and central sensitization via its main receptor CXCR2, which is a promising target for novel analgesic drugs. Here, we reviewed and discussed the role of the CXCL1/CXCR2 signaling axis in pathological pain conditions triggered by either peripheral inflammation or nerve injury.


Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Quimiocina CXCL1/metabolismo , Dor , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , Dor/etiologia , Dor/metabolismo , Dor/patologia , Traumatismos dos Nervos Periféricos/complicações
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