•The vagus nerve controls inflammation and organ injury by regulating the production of inflammatory factors in the spleen.•Most studies showed absence of neurogenic cholinergic markers in the ...spleen.•Recent studies suggest that vagal regulation of inflammation is mediated by multi-synaptic interactions between the vagus and the splanchnic nerves.•These mechanisms are allowing the design of novel therapeutic strategies for infectious and inflammatory disorders.
The vagus nerve coordinates most physiologic functions including the cardiovascular and immune systems. This mechanism has significant clinical implications because electrical stimulation of the vagus nerve can control inflammation and organ injury in infectious and inflammatory disorders. The complex mechanisms that mediate vagal modulation of systemic inflammation are mainly regulated via the spleen. More specifically, vagal stimulation prevents organ injury and systemic inflammation by inhibiting the production of cytokines in the spleen. However, the neuronal regulation of the spleen is controversial suggesting that it can be mediated by either monosynaptic innervation of the splenic parenchyma or secondary neurons from the celiac ganglion depending on the experimental conditions. Recent physiologic and anatomic studies suggest that inflammation is regulated by neuro-immune multi-synaptic interactions between the vagus and the splanchnic nerves to modulate the spleen. Here, we review the current knowledge on these interactions, and discuss their experimental and clinical implications in infectious and inflammatory disorders.
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•Neutrophils are an immunological and diffuse source of neurotransmitters.•Neutrophils regulate sensory neuron functions and vice-versa.•Neutrophils play a crucial role in ...inflammatory disorders in the central nervous system.
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.
Sepsis, an overwhelming inflammatory response syndrome secondary to infection, is one of the costliest and deadliest medical conditions worldwide. Neutrophils are classically considered to be ...essential players in the host defense against invading pathogens. However, several investigations have shown that impairment of neutrophil migration to the site of infection, also referred to as neutrophil paralysis, occurs during severe sepsis, resulting in an inability of the host to contain and eliminate the infection. On the other hand, the neutrophil antibacterial arsenal contributes to tissue damage and the development of organ dysfunction during sepsis. In this review, we provide an overview of the main events in which neutrophils play a beneficial or deleterious role in the outcome of sepsis.
ABSTRACT
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 β2‐adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either β2‐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 β2‐agonists to control inflammation in both β2‐knockout and nude mice. β2‐Agonists inhibit cytokine production in splenocytes (IC50~1 μM) and prevent systemic inflammation in wild‐type but not in β2‐knockout mice. β2‐Agonists rescue wild‐type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti‐inflammatory potential of β2‐agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in β2‐knockout mice. These results indicate that β2‐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.—Vida, G., Peña, G., Kanashiro, A., del Rocio Thompson‐Bonilla, M., Palange, D., Deitch, E. A., Ulloa, L. β2‐Adrenore‐ceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system. FASEB J. 25, 4476–4485 (2011). www.fasebj.org
The present study examined the hemodynamics arterial pressure (AP), AP variability (APV), heart rate (HR), and heart rate variability (HRV), cardiac function (echocardiographycally), and myocardial ...inflammation in Balb/c mice submitted to Periodontitis, through the ligation of the left first molar, or Sham surgical procedure. The first protocol indicated that the AP was similar (136 ± 2 vs. 132 ± 3 mmHg in Sham), while the HR was higher in mice with Periodontitis (475 ± 20 vs. 412 ± 18 bpm in Sham), compared to their Sham counterparts. The APV was higher in mice with Periodontitis when evaluated in the time domain (4.5 ± 0.3 vs. 3.4 ± 0.2 mmHg in Sham), frequency domain (power of the LF band of systolic AP), or through symbolic analysis (patterns 0V + 1V), indicating a sympathetic overactivity. The HRV was similar in the mice with Periodontitis, as compared to their Sham counterparts. In the second protocol, the mice with Periodontitis showed decreased cardiac output (10 ± 0.8 vs. 15 ± 1.4 mL/min in Sham) and ejection fraction (37 ± 3 vs. 47 ± 2% in Sham) associated with increased myocardial cytokines (Interleukin-17, Interleukin-6, and Interleukin-4). This study shows that experimental Periodontitis caused cardiac dysfunction, increased heart cytokines, and sympathetic overactivity, in line with epidemiological studies indicating an increased risk of cardiovascular events in clinical Periodontitis.
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.
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).
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.
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-1β, and TNF-α spinal levels.
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.
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.
Highlights • A novel afferent vagal signaling improves local inflammatory response in arthritis. • This new neural pathway depends on sympatho-excitatory brain areas activation. • Local ...norepinephrine release modulates inflammation after sympathetic activation.
Sepsis is a leading cause of death in hospitalized patients. Many experimental treatments may have failed in clinical trials for sepsis, in part, because they focused on immune responses of healthy ...animals that did not mimic the metabolic settings of septic patients. Epidemiological studies show an association between metabolic and immune alterations and over 1/3 of septic patients are diabetic, but the mechanism linking these systems is unknown. Here, we report that metabolic fasting increased systemic inflammation and worsened survival in experimental sepsis. Feeding and administration of glucose in fasted mice activated the vagal tone without affecting blood pressure. Vagal stimulation attenuated hyperglycemia and serum TNF levels in sham but only hyperglycemia in splenectomized mice. Vagal stimulation induced the production of dopamine from the adrenal glands. Experimental diabetes increased hyperglycemia and systemic inflammation in experimental sepsis. Fenoldopam, a specific dopaminergic type-1 agonist, attenuated hyperglycemia and systemic inflammation in diabetic endotoxemic mice. These results indicate that glucose activates vagal control of hyperglycemia and inflammation in fasted septic mice via dopamine.
Baroreflex and chemoreflex act through the autonomic nervous system, which is involved with the neural regulation of inflammation. The present study reports the effects of reflex physiological ...sympathetic activation in endotoxemic rats using bilateral carotid occlusion (BCO), a physiological approach involving the baroreflex and chemoreflex mechanisms and the influence of the baroreceptors and peripheral chemoreceptors in the cardiovascular and systemic inflammatory responses. After lipopolysaccharide (LPS) administration, the arterial pressure was recorded during 360 min in unanesthetized rats, and serial blood samples were collected to analyze the plasma cytokine levels. BCO elicited the reflex activation of the sympathetic nervous system, providing the following outcomes: (I) increased the power of the low-frequency band in the spectrum of the systolic arterial pressure during the BCO period; (II) reduced the levels of pro-inflammatory cytokines in plasma, including the tumor necrosis factor (TNF) and the interleukin (IL)-1
; (III) increased the plasma levels of anti-inflammatory cytokine IL-10, 90 min after LPS administration. Moreover, selective baroreceptor or chemoreceptor denervation deactivated mechanosensitive and chemical sensors, respectively, and decreased the release of the LPS-induced cytokine but did not alter the BCO modulatory effects. These results show, for the first time, that physiological reflex activation of the sympathetic circuit decreases the inflammatory response in endotoxemic rats and suggest a novel function for the baroreceptors as immunosensors during the systemic inflammation.
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