RESUMEN
Environment enrichment (EE) is a well-known eustress model showing beneficial effects in different psychiatric diseases, but its positive properties in panic disorders are not yet established. The confrontation between prey and predator in complex arenas has been validated as a putative panic attack model. The principal aim of this work was to investigate the role of the EE on panic-like defensive responses elicited by mice threatened by venomous snakes. After 6 weeks of exposure either to an enriched or standard environments, 36 male mice were habituated in a complex polygonal arena for snakes containing an artificial burrow and elevated platforms for escape. The animals were confronted by Bothrops jararaca for 5 min, and the following antipredatory responses were recorded: defensive attention, stretched attend posture, flat back approach, prey versus predator interaction, oriented escape behavior, time spent in a safe place, and number of crossings. Mice threatened by snakes displayed several antipredatory reactions as compared to the exploratory behavior of those animals submitted to a nonthreatening situation (toy snake) in the same environment. Notably, EE causes anxiolytic- and panicolytic-like effects significantly decreasing the defensive attention and time spent in safe places and significantly increasing both prey versus predator interaction and exploratory behavior. In conclusion, our data demonstrate that EE can alter the processing of fear modulation regarding both anxiety- and panic-like responses in a dangerous condition, significantly modifying the decision-making defensive strategy.
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Crotalinae , Trastorno de Pánico , Ratones , Masculino , Animales , Bothrops jararaca , Miedo , Pánico/fisiologíaRESUMEN
The sympathetic arm of the inflammatory reflex is the efferent pathway through which the central nervous system (CNS) can control peripheral immune responses. Diminazene aceturate (DIZE) is an antiparasitic drug that has been reported to exert protective effects on various experimental models of inflammation. However, the pathways by which DIZE promotes a protective immunomodulatory effects still need to be well established, and no studies demonstrate the capacity of DIZE to modulate a neural reflex to control inflammation. C57BL/6 male mice received intraperitoneal administration of DIZE (2 mg/Kg) followed by lipopolysaccharide (LPS, 5 mg/Kg, i.p.). Endotoxemic animals showed hyperresponsiveness to inflammatory signals, while those treated with DIZE promoted the activation of the inflammatory reflex to attenuate the inflammatory response during endotoxemia. The unilateral cervical vagotomy did not affect the anti-inflammatory effect of DIZE in the spleen and serum. At the same time, splenic denervation attenuated tumor necrosis factor (TNF) synthesis in the spleen and serum. Using broad-spectrum antibiotics for two weeks showed that LPS modulated the microbiota to induce a pro-inflammatory profile in the intestine and reduced the serum concentration of tryptophan and serotonin (5-HT), while DIZE restored serum tryptophan and increased the hypothalamic 5-HT levels. Furthermore, the treatment with 4-Chloro-DL-phenylalanine (pcpa, an inhibitor of 5-HT synthesis) abolished the anti-inflammatory effects of the DIZE in the spleen. Our results indicate that DIZE promotes microbiota modulation to increase central 5-HT levels and activates the efferent sympathetic arm of the inflammatory reflex to control splenic TNF production in endotoxemic mice.
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Diminazeno , Endotoxemia , Microbioma Gastrointestinal , Inflamación , Lipopolisacáridos , Ratones Endogámicos C57BL , Serotonina , Bazo , Sistema Nervioso Simpático , Animales , Masculino , Ratones , Bazo/metabolismo , Bazo/efectos de los fármacos , Diminazeno/análogos & derivados , Diminazeno/farmacología , Lipopolisacáridos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/metabolismo , Serotonina/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Endotoxemia/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Antiinflamatorios/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients' outcomes.
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Neoplasias , Neuroglía , Humanos , Estudios Retrospectivos , Neuroglía/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patología , Pericitos , Microambiente Tumoral/fisiología , Neoplasias/patologíaRESUMEN
OBJECTIVE: This study aimed to investigate the effects of FK506 on experimental sepsis immunopathology. It investigated the effect of FK506 on leukocyte recruitment to the site of infection, systemic cytokine production, and organ injury in mice with sepsis. METHODS: Using a murine cecal ligation and puncture (CLP) peritonitis model, the experiments were performed with wild-type (WT) mice and mice deficient in the gene Nfat1 (Nfat1-/-) in the C57BL/6 background. Animals were treated with 2.0 mg/kg of FK506, subcutaneously, 1 h before the sepsis model, twice a day (12 h/12 h). The number of bacteria colony forming units (CFU) was manually counted. The number of neutrophils in the lungs was estimated by the myeloperoxidase (MPO) assay. The expression of CXCR2 in neutrophils was determined using flow cytometry analysis. The expression of inflammatory cytokines in macrophage was determined using ELISA. The direct effect of FK506 on CXCR2 internalization was evaluated using HEK-293T cells after CXCL2 stimulation by the BRET method. RESULTS: FK506 treatment potentiated the failure of neutrophil migration into the peritoneal cavity, resulting in bacteremia and an exacerbated systemic inflammatory response, which led to higher organ damage and mortality rates. Failed neutrophil migration was associated with elevated CXCL2 chemokine plasma levels and lower expression of the CXCR2 receptor on circulating neutrophils compared with non-treated CLP-induced septic mice. FK506 did not directly affect CXCL2-induced CXCR2 internalization by transfected HEK-293 cells or mice neutrophils, despite increasing CXCL2 release by LPS-treated macrophages. Finally, the CLP-induced response of Nfat1-/- mice was similar to those observed in the Nfat1+/+ genotype, suggesting that the FK506 effect is not dependent on the NFAT1 pathway. CONCLUSION: Our data indicate that the increased susceptibility to infection of FK506-treated mice is associated with failed neutrophil migration due to the reduced membrane availability of CXCR2 receptors in response to exacerbated levels of circulating CXCL2.
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Neutrófilos , Sepsis , Humanos , Ratones , Animales , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Células HEK293 , Ratones Endogámicos C57BL , Sepsis/metabolismo , Infiltración NeutrófilaRESUMEN
Bioelectronic medicine is a novel field in modern medicine based on the specific neuronal stimulation to control organ function, cardiovascular, and immune homeostasis. However, most studies addressing neuromodulation of the immune system have been conducted on anesthetized animals, which can affect the nervous system and neuromodulation. Here, we review recent studies involving conscious experimental rodents (rats and mice) to better understand the functional organization of neural control of immune homeostasis. We highlight typical experimental models of cardiovascular regulation, such as electrical activation of the aortic depressor nerve or the carotid sinus nerve, bilateral carotid occlusion, the Bezold-Jarisch reflex, and intravenous administration of the bacterial endotoxin lipopolysaccharide. These models have been used to investigate the relationship between neuromodulation of the cardiovascular and immune systems in conscious rodents (rats and mice). These studies provide critical information about the neuromodulation of the immune system, particularly the role of the autonomic nervous system, i.e., the sympathetic and parasympathetic branches acting both centrally (hypothalamus, nucleus ambiguus, nucleus tractus solitarius, caudal ventrolateral medulla, and rostral ventrolateral medulla), and peripherally (particularly spleen and adrenal medulla). Overall, the studies in conscious experimental models have certainly highlighted to the reader how the methodological approaches used to investigate cardiovascular reflexes in conscious rodents (rats and mice) can also be valuable for investigating the neural mechanisms involved in inflammatory responses. The reviewed studies have clinical implications for future therapeutic approaches of bioelectronic modulation of the nervous system to control organ function and physiological homeostasis in conscious physiology.
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Inflamación , Núcleo Solitario , Ratas , Ratones , Animales , Núcleo Solitario/fisiología , Neuronas , Sistema Nervioso Autónomo , Hipotálamo , Sistema Nervioso Simpático , Frecuencia Cardíaca/fisiología , Presión Sanguínea/fisiologíaRESUMEN
Recent evidence has suggested that the carotid bodies might act as immunological sensors, detecting pro-inflammatory mediators and signalling to the central nervous system, which, in turn, orchestrates autonomic responses. Here, we confirmed that the TNF-α receptor type I is expressed in the carotid bodies of rats. The systemic administration of TNF-α increased carotid body afferent discharge and activated glutamatergic neurons in the nucleus tractus solitarius (NTS) that project to the rostral ventrolateral medulla (RVLM), where many pre-sympathetic neurons reside. The activation of these neurons was accompanied by an increase in splanchnic sympathetic nerve activity. Carotid body ablation blunted the TNF-α-induced activation of RVLM-projecting NTS neurons and the increase in splanchnic sympathetic nerve activity. Finally, plasma and spleen levels of cytokines after TNF-α administration were higher in rats subjected to either carotid body ablation or splanchnic sympathetic denervation. Collectively, our findings indicate that the carotid body detects circulating TNF-α to activate a counteracting sympathetic anti-inflammatory mechanism.
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Cuerpo Carotídeo , Animales , Antiinflamatorios , Bulbo Raquídeo/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo , Núcleo Solitario/fisiología , Sistema Nervioso Simpático/fisiología , Factor de Necrosis Tumoral alfaRESUMEN
INTRODUCTION: Environmental enrichment (EE) is a useful and sophisticated tool that improves rodents' well-being by stimulating social behaviour and cognitive, motor, and sensory functions. Exposure to EE induces neuroplasticity in different brain areas, including the limbic system, which has been implicated in the control of anxiety and fear. However, the effects of EE on ethologically relevant naturalistic behaviours, such as those displayed by prey in the presence of predators, remain largely unexplored. MATERIAL AND METHODS: In the present study, we investigated anxiety- and panic attack-like behaviours in a predator (cat)-prey confrontation paradigm and compared them with those in classical assays, such as the elevated plus-maze (EPM), marble-burying, and open field tests (OFTs), using C57BL/6J male mice housed in enriched or standard environments for 6 weeks. RESULTS: We observed that EE exposure caused enhancement of the levels of anxiety-like behaviours in the EPM and OFTs, increasing risk assessment (an anxiety-related response), and decreasing escape (a panic attack-like response) behaviours during exposure to the predator versus prey confrontation paradigm. CONCLUSION: Taken together, our findings suggest that enriched external environments can modify the processing of fear- and anxiety-related stimuli in dangerous situations, changing the decision-making defensive strategy.
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Ansiedad , Trastorno de Pánico , Animales , Trastornos de Ansiedad/psicología , Conducta Animal/fisiología , Miedo/fisiología , Miedo/psicología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Angiotensin-(1-7) [Ang-(1-7)] is an angiotensin-derived neuropeptide with potential anti-hypertensive and anti-inflammatory properties. However, a possible action of Ang-(1-7) in neuroimmune interactions to regulate inflammatory response has not been explored. Thus, the aim of this study was to determine whether the intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation via sympathetic efferent circuits. Wistar male rats received systemic administration of lipopolysaccharide (LPS) (1.5 mg/Kg). Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of splenic norepinephrine and attenuated tumor necrosis factor (TNF) and nitric oxide (NO), but increased interleukin-10 (IL-10), levels in the serum, spleen, and liver in endotoxemic rats. Furthermore, 6-hydroxydopamine-induced chemical sympathectomy (100 mg/Kg, intravenous) or i.c.v. administration of Mas receptor antagonist A779 (3 nmol in 2 µL) abolished the anti-inflammatory effects of central Ang-(1-7) injection. Moreover, this treatment did not alter the plasmatic LPS-induced corticosterone and vasopressin. The administration of Ang-(1-7) reverted the low resistance in response to catecholamines of rings of thoracic aorta isolated from endotoxemic rats, treated or not, with this peptide by a mechanism dependent on the regulation of NO released from perivascular adipose tissue. Together, our results indicate that Ang-(1-7) regulates systemic inflammation and vascular hyporesponsiveness in endotoxemia via activation of a central Mas receptors/sympathetic circuits/norepinephrine axis and provide novel mechanistic insights into the anti-inflammatory Ang-(1-7) properties.
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Endotoxemia , Angiotensina I , Animales , Endotoxemia/tratamiento farmacológico , Masculino , Fragmentos de Péptidos , Ratas , Ratas WistarRESUMEN
Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil's functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.
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Neuroinmunomodulación , Neutrófilos/inmunología , Animales , Humanos , Inmunidad Innata , Inflamación/inmunología , Neurotransmisores/inmunología , Nocicepción , Dolor/inmunología , Células Receptoras Sensoriales/inmunologíaRESUMEN
The gastrointestinal (GI) tract harbors commensal microorganisms as well as invasive bacteria, toxins and other pathogens and, therefore, plays a pivotal barrier and immunological role against pathogenic agents. The vagus nerve is an important regulator of the GI tract-associated immune system, having profound effects on inflammatory responses. Among GI tract organs, the liver is a key site of immune surveillance, as it has a large population of resident macrophages and receives the blood drained from the guts through the hepatic portal circulation. Although it is widely accepted that the hepatic tissue is a major target for vagus nerve fibers, the role of this neural circuit in liver immune functions is still poorly understood. Herein we used in vivo imaging techniques, including confocal microscopy and scintigraphy, to show that vagus nerve stimulation increases the phagocytosis activity by resident macrophages in the liver, even on the absence of an immune challenge. The activation of this neural circuit in a non-lethal model of sepsis optimized the removal of bacteria in the liver and resulted in the production of anti-inflammatory and pro-regenerative cytokines. Our findings provide new insights into the neural regulation of the immune system in the liver.
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Hígado/inmunología , Fagocitosis/fisiología , Nervio Vago/fisiología , Animales , Citocinas , Femenino , Tracto Gastrointestinal , Hígado/patología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Fagocitos/metabolismo , Sepsis/inmunología , Nervio Vago/patología , Estimulación del Nervio Vago/métodosRESUMEN
OBJECTIVE AND DESIGN: The objective of this study was to investigate the role of Nod1 in the recruitment of neutrophils into the infection site and in the establishment of the inflammatory response elicited by a clinical isolate strain of P. aeruginosa in vivo, while comparing it to the well-established role of MyD88 in this process. SUBJECTS: Wild-type, Nod1-/- and MyD88-/- mice, all with a C57Bl/6 background. METHODS: Mice were intranasally infected with Pseudomonas aeruginosa DZ605. Bronchoalveolar lavage and blood were harvested 6 or 20 h post-infection for evaluating bacterial load, chemokine levels and neutrophil migration. Survival post-infection was also observed. RESULTS: We show here that wild-type and Nod1-/- mice induce similar lung chemokine levels, neutrophil recruitment, and bacterial load, thus leading to equal survival rates upon P. aeruginosa pulmonary infection. Furthermore, we confirmed the essential role of MyD88-dependent signalling in recruiting neutrophils and controlling P. aeruginosa-induced pulmonary infection. CONCLUSION: The results suggest that in contrast to MyD88, under our experimental conditions, the absence of Nod1 does not impair the recruitment of neutrophils in response to P. aeruginosa DZ605.
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Factor 88 de Diferenciación Mieloide/genética , Proteína Adaptadora de Señalización NOD1/genética , Infecciones por Pseudomonas/genética , Pseudomonas aeruginosa , Animales , Bacteriemia/microbiología , Líquido del Lavado Bronquioalveolar/microbiología , Quimiocinas/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/genética , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidad , Transducción de Señal/genéticaRESUMEN
Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations.
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Artritis Experimental/terapia , Locus Coeruleus/fisiopatología , Núcleo Hipotalámico Paraventricular/fisiopatología , Estimulación del Nervio Vago , Antagonistas Adrenérgicos beta/administración & dosificación , Vías Aferentes/fisiopatología , Animales , Artritis Experimental/fisiopatología , Artritis Reumatoide/fisiopatología , Artritis Reumatoide/terapia , Estimulación Eléctrica , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/metabolismo , Ratas Wistar , Sistema Nervioso Simpático/fisiopatología , Canales Catiónicos TRPV/genéticaRESUMEN
Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called "cholinergic anti-inflammatory pathway", suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.
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Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Colinérgicos/farmacología , Colinérgicos/uso terapéutico , Sepsis/tratamiento farmacológico , Animales , Humanos , Sistema Inmunológico/efectos de los fármacos , Inflamación/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Nervio Vago/efectos de los fármacosRESUMEN
BACKGROUND/PURPOSE: Recent studies have reported that sepsis survivors show impaired central nervous system functions. The osmoregulation in this post-sepsis condition has not been well investigated. In the present study, we evaluated the secretion of neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin (OT), and water intake induced by osmotic challenge in survivor rats. METHODS: Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP). Five days after CLP surgery, the survivor and naive animals were stimulated with an osmotic challenge consisting of hypertonic saline administration. Thirty minutes later, blood and brain were collected for determination of osmolality, nitrite, interleukin (IL)-1ß, IL-6, AVP and OT levels and c-fos expression analysis of hypothalamic supraoptic nuclei (SON), respectively. In another set of sepsis survivor animals, water intake was measured for 240 min after the osmotic stimulus. RESULTS: High levels of nitrite and IL-1ß, but not IL-6, were found in the plasma of sepsis survivors and this long-term systemic inflammation was not altered by the osmotic challenge. Moreover, the AVP and OT secretion (but not the osmolality) and c-fos expression in SON were significantly attenuated in CLP survivor animals. Additionally, there was no alteration in the water intake response induced by osmotic challenge in the sepsis survivor group. CONCLUSION: The results suggest that the inflammatory components mediated a persistent impairment in the component of the osmoregulatory reflex affecting the secretion of neurohypophyseal hormones in sepsis survivor animals.
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Sepsis/sangre , Animales , Hipotálamo/metabolismo , Interleucina-1beta/sangre , Interleucina-6/sangre , Nitritos/sangre , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas WistarRESUMEN
The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1ß and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation.
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Artritis/fisiopatología , Barorreflejo , Inflamación/fisiopatología , Articulación de la Rodilla/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adrenalectomía , Animales , Artritis/inducido químicamente , Artritis/metabolismo , Modelos Animales de Enfermedad , Estimulación Eléctrica , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Articulación de la Rodilla/patología , Masculino , Neutrófilos/metabolismo , Ratas , Ratas Wistar , Esplenectomía , Vagotomía , ZimosanRESUMEN
Introduction: Chemotherapy-induced neuropathic pain (CINP) is one of the main adverse effects of chemotherapy treatment. At the spinal level, CINP modulation involves glial cells that upregulate Toll-like receptor 4 (TLR4) and signaling pathways, which can be activated by pro-inflammatory mediators as the high mobility group box-1 (HMGB1). Objective: To evaluate the spinal role of HMGB1 in the paclitaxel-induced neuropathic pain via receptor for advanced glycation end products (RAGE) and TLR4 activation expressed in glial cells. Methods: Male C57BL/6 Wild type and TLR4 deficient mice were used in the paclitaxel-induced neuropathic pain model. The nociceptive threshold was measured using the von Frey filament test. In addition, recombinant HMGB1 was intrathecally (i.t.) injected to confirm its nociceptive potential. To evaluate the spinal participation of RAGE, TLR4, NF-kB, microglia, astrocytes, and MAPK p38 in HMGB1-mediated nociceptive effect during neuropathic pain and recombinant HMGB1-induced nociception, the drugs FPS-ZM1, LPS-RS, PDTC, minocycline, fluorocitrate, and SML0543 were respectively administrated by i.t. rout. Microglia, astrocytes, glial cells, RAGE, and TLR4 protein expression were analyzed by Western blot. ELISA immunoassay was also used to assess HMGB1, IL-1ß, and TNF-α spinal levels. Results: The pharmacological experiments demonstrated that spinal RAGE, TLR4, microglia, astrocytes, as well as MAPK p38 and NF-kB signaling are involved with HMGB1-induced nociception and paclitaxel-induced neuropathic pain. Furthermore, HMGB1 spinal levels were increased during the early stages of neuropathic pain and associated with RAGE, TLR4 and microglial activation. RAGE and TLR4 blockade decreased spinal levels of pro-inflammatory cytokines during neuropathic pain. Conclusion: Taken together, our findings indicate that HMGB1 may be released during the early stages of paclitaxel-induced neuropathic pain. This molecule activates RAGE and TLR4 receptors in spinal microglia, upregulating pro-inflammatory cytokines that may contribute to neuropathic pain.
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Proteína HMGB1 , Neuralgia , Animales , Masculino , Ratones , Citocinas/metabolismo , Proteína HMGB1/metabolismo , Hiperalgesia/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuralgia/inducido químicamente , Neuralgia/metabolismo , FN-kappa B , Paclitaxel/toxicidad , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Recent evidence has suggested that changes in maternal gut microbiota in early life may generate neurobiological consequences associated with psychiatric-related abnormalities. However, the number of studies on humans investigating this problem is limited, and preclinical findings sometimes conflict. Therefore, we run a meta-analysis to examine whether maternal microbiota disturbance (MMD) during neurodevelopment might affect the offspring during adulthood. We found thirteen studies, from a set of 459 records selected by strategy registered on PROSPERO (#289224), to target preclinical studies that evaluated the behavioral outcomes of the rodents generated by dams submitted to perinatal enteric microbiota perturbation. The analysis revealed a significant effect size (SMD = -0.51, 95% CI = -0.79 to -0.22, p < .001, T2 = 0.54, I2 = 79.85%), indicating that MMD might provoke behavioral impairments in the adult offspring. The MMD also induces a significant effect size for the reduction of the sociability behavior (SMD = -0.63, 95% CI = -1.18 to -0.07, p = 0.011, T2 = 0.30, I2 = 76.11%) and obsessive-compulsive-like behavior (SMD = -0.68, 95% CI = -0.01 to -1.36, p = 0.009, T2 = 0.25, I2 = 62.82%) parameters. The effect size was not significant or inconclusive for memory and anxiety-like behavior, or inconclusive for schizophrenia-like and depressive-like behavior. Therefore, experimental perinatal MMD is vertically transmitted to the offspring, negatively impacting behavioral parameters related to psychiatric disorders.
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Microbioma Gastrointestinal , Trastornos Mentales , Microbiota , Femenino , Adulto , Embarazo , Humanos , AnsiedadRESUMEN
Hematopoietic stem cells are maintained in a specialized microenvironment, known as the 'niche', within the bone marrow. Understanding the contribution of cellular and molecular components within the bone marrow niche for the maintenance of hematopoietic stem cells is crucial for the success of therapeutic applications. So far, the roles of crucial mechanisms within the bone marrow niche have been explored in transgenic animals in which genetic modifications are ubiquitously introduced in the whole body. The lack of precise tools to explore genetic alterations exclusively within the bone marrow prevents our determination of whether the observed outcomes result from confounding effects from other organs. Here, we developed a new method - 'whole bone subcutaneous transplantation'- to study the bone marrow niche in transgenic animals precisely. Using immunolabeling of CD45.1 (donor) vs. CD45.2 (recipient) hematopoeitic stem cells, we demonstrated that hematopoeitic stem cells from the host animals colonize the subcutaneously transplanted femurs after transplantation, while the hematopoietic stem cells from the donor disappear. Strikinlgy, the bone marrow niche of these subcutaneously transplanted femurs remain from the donor mice, enabling us to study specifically cells of the bone marrow niche using this model. We also showed that genetic ablation of peri-arteriolar cells specifically in donor femurs reduced the numbers of hematopoietic stem cells in these bones. This supports the use of this strategy as a model, in combination with genetic tools, to evaluate how bone marrow niche specific modifications may impact non-modified hematopoietic stem cells. Thus, this approach can be utilized for genetic manipulation in vivo of specific cell types only within the bone marrow. The combination of whole bone subcutaneous transplantation with rodent transgenic models will facilitate a more precise, complex and comprehensive understanding of existing problems in the study of the hematopoietic stem cell bone marrow niche.
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Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Ratones , Animales , Células Madre Hematopoyéticas/metabolismo , Trasplante de Médula Ósea , HuesosRESUMEN
The nervous system is classically organized into sympathetic and parasympathetic systems acting in opposition to maintain physiological homeostasis. Here, we report that both systems converge in the activation of ß2-adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either ß2-knockout or lymphocyte-deficient nude mice. Unlike typical suppressor CD25(+) cells, the transfer of CD4(+)CD25(-) regulatory lymphocytes reestablishes the anti-inflammatory potential of the vagus nerve and ß2-agonists to control inflammation in both ß2-knockout and nude mice. ß2-Agonists inhibit cytokine production in splenocytes (IC(50)≈ 1 µM) and prevent systemic inflammation in wild-type but not in ß2-knockout mice. ß2-Agonists rescue wild-type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti-inflammatory potential of ß2-agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in ß2-knockout mice. These results indicate that ß2-adrenoceptors in regulatory lymphocytes are critical for the anti-inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.
Asunto(s)
Inmunidad Innata , Neuroinmunomodulación , Receptores Adrenérgicos beta 2/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Citocinas/biosíntesis , Endotoxemia/inmunología , Endotoxemia/fisiopatología , Hemodinámica , Inflamación/inmunología , Inflamación/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 2/deficiencia , Receptores Adrenérgicos beta 2/genética , Sepsis/inmunología , Sepsis/fisiopatología , Linfocitos T Reguladores/efectos de los fármacos , Factor de Necrosis Tumoral alfa/sangre , Nervio Vago/inmunologíaRESUMEN
The idea that the nervous system communicates with the immune system to regulate physiological and pathological processes is not new. However, there is still much to learn about how these interactions occur under different conditions. The carotid body (CB) is a sensory organ located in the neck, classically known as the primary sensor of the oxygen (O2) levels in the organism of mammals. When the partial pressure of O2 in the arterial blood falls, the CB alerts the brain which coordinates cardiorespiratory responses to ensure adequate O2 supply to all tissues and organs in the body. A growing body of evidence, however, has demonstrated that the CB is much more than an O2 sensor. Actually, the CB is a multimodal sensor with the extraordinary ability to detect a wide diversity of circulating molecules in the arterial blood, including inflammatory mediators. In this review, we introduce the literature supporting the role of the CB as a critical component of neuroimmune interactions. Based on ours and other studies, we propose a novel neuroimmune pathway in which the CB acts as a sensor of circulating inflammatory mediators and, in conditions of systemic inflammation, recruits a sympathetic-mediated counteracting mechanism that appears to be a protective response.