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Abstract Background While the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain-Barre syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use. Methods APN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve. Results TLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8+ T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms. Conclusion The study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.

Abstract Background Though it is well-known that a high-salt diet (HSD) is associated with many chronic diseases, the effects of long-term high-salt intake on physiological functions and homeostasis remain elusive. In this study, we investigated whether and how an HSD affects mouse nociceptive thresholds, and myeloid cell trafficking and activation. Methods Healthy C57BL/6 male and female mice were fed an HSD (containing 4% NaCl in chow and 1% NaCl in water) from the time of weaning for 3 to 4 months. Circulating monocytes, nerve macrophages, spinal microglia, and associated inflammatory responses were scrutinized using flow cytometry, immunohistochemistry, and quantitative real-time polymerase chain reaction (qPCR) approaches. Mouse pain sensitivity to mechanical stimuli was monitored with von Frey tests along the experimental duration. Results Mice on an HSD have reduced mechanical thresholds. They feel more pain than those on a normal diet (ND), e.g., regular laboratory chow (0.3% NaCl in chow). An HSD induced not only a remarkable expansion of circulating monocytes, CCR2+Ly6Chi inflammatory monocytes in particular, but also an accumulation of CD11b+F4/80+ macrophages in the peripheral nerves and an activation of Iba-1+ spinal microglia. Replacing an HSD with a ND was unable to reverse the HSD-induced mechanical hypersensitivity or rescue the altered immune responses. However, treating HSD-fed mice with a chemokine receptor CCR2 antagonist effectively normalized the pain thresholds and immune cell profile in the periphery and spinal cord. An HSD failed to alter pain thresholds and myeloid cell activation in CCR2-deficient mice. Spinal microglial activation is required for HSD-induced mechanical hypersensitivity in male, but not in female mice. Conclusion Overall, this study provides evidence that an HSD has a long-term impact on physiological function. CCR2-mediated cellular response, including myeloid cell trafficking and associated inflammation, plays pivotal roles in salt-dietary modulation of pain sensitivity.

One hallmark of Guillain-Barre syndrome (GBS), a prototypic autoimmune peripheral neuropathy (APN) is infiltration of leukocytes (macrophages and T cells) into peripheral nerves, where chemokines and their receptors play major roles. In this study, we aimed to understand the potential contribution of chemokine receptors CCR2 and CX3CR1 in APN by using a well-established mouse model, B7.2 transgenic (L31) mice, which possesses a predisposed inflammatory background. We crossbred respectively CCR2KO and CX3CR1KO mice with L31 mice. The disease was initiated by partial ligation on one of the sciatic nerves. APN pathology and neurological function were evaluated on the other non-ligated sciatic nerve/limb. Our results revealed that L31/CX3CR1KO but not L31/CCR2KO mice were resistant to APN. CX3CR1 is needed for maintaining circulating monocyte and CD8+ T cell survival. While migration of a significant number of activated CD8+ T cells to peripheral nerves is essential in autoimmune response in nerve, recruitment of monocytes into PNS seems optional. Disease onset is independent of CCR2 mediated blood-derived macrophage recruitment, which can be replaced by compensatory proliferation of resident macrophages in peripheral nerve. CX3CR1 could also contribute to APN via its critical involvement in maintaining nerve macrophage phagocytic ability. We conclude that blockade of CX3CR1 signaling may represent an interesting anti-inflammatory strategy to improve therapeutic management for GBS patients.

Summary: Regulatory T (Treg) cells integrate diverse environmental signals to modulate their function for optimal suppression. Translational regulation represents a favorable mechanism for Treg cell environmental sensing and adaptation. In this study, we carry out an unbiased screen of the Treg cell translatome and identify serum/glucocorticoid-regulated kinase 1 (SGK1), a known salt sensor in T cells, as being preferentially translated in activated Treg cells. We show that high salt (HS) drives thymic Treg cells to adopt a T helper type 17 (Th17)-like phenotype and enhances generation of Th17-like induced Treg cells in a SGK1-dependent manner, all the while maintaining suppressive function. Salt-mediated Th17-like differentiation of Treg cells was evident in mice fed with HS diet or injected with HS-preconditioned T cells. Overall, SGK1 enables Treg cells to adapt their function in response to environmental cues. By understanding these environmental-sensing mechanisms, we envision targeted approaches to fine-tune Treg cell function for better control of inflammation. : Yang et al. demonstrate that high salt promotes Th17-like functional adaptation of both thymic and induced Foxp3+ Treg cell subsets through a salt-sensor protein, SGK1. The translationally regulated SGK1 pathway enables Treg cells to fine-tune their effector function in response to environmental cues during the dynamic course of inflammation. Keywords: Foxp3+ Treg cell, Treg Adaptation, Treg Reprogramming, salt, SGK1, Treg cell plasticity, mRNA translation regulation, Environmental Sensing, Autoimmunity, RORγt+ Treg, Helios

Introduction/Aim: Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy are prototypic autoimmune peripheral neuropathy (APN) which represent a serious neurological emergency. Although current treatment options have proven effective, many patients still present with a severe disease course, pain and residual deficits. We have reported that B7.2 transgenic L31 mice spontaneously develop inflammatory peripheral neuropathy. We also showed that an injury to peripheral nerve in L31 mice facilitates the development of APN. Both effector/memory CD8 T cells and B7.2+ macrophages are required for disease initiation. Here, we highlighted the importance of CX3CR1 expression in disease pathogenesis and in the development of pain like behavior in L31 mice. Methods: L31 mice were crossed with CX3CR1KO mice, and the effect on macrophage phagocytic ability, activated CD8 T cells function and pathology were assessed. Results: CX3CR1 expression was strongly upregulated in sciatic nerve of symptomatic L31 mice which correlated with increased phagocytic ability. Enhanced phagocytosis in L31 mice was impeded in L31/CX3CR1−/- mice. Also, injury failed to trigger APN in L31 mice deficient of CX3CR1 expression. APN associated sensory deficits positively correlated with the amount of CX3CR1 expression. In addition, CX3CR1 deficiency led to a high number of dying monocytes, macrophages and activated CD8 T cells suggesting that CX3CR1 signaling may be crucial for their survival. Lastly, sciatic nerve histology showed no myelin and axon damage in L31/CX3CR1−/- mice. Discussion/Conclusions: These data suggest that CX3CR1 expression are critical for the development of APN in L31 mice. CX3CR1 expressing macrophages contribute to disease pathogenesis via enhanced antigen phagocytosis and presentation.

Introduction/Aim: Though several studies have shown that high salt diet (HSD) is related to the development of chronic diseases, the effect of long-term high-salt intake on the immune system and pain behavior remains elusive. Here, we aimed to investigate whether and how HSD affected mouse pain thresholds and innate immunity, especially myeloid cells. Methods: Healthy C57BL/6 male and female mice were fed with HSD (containing 4% NaCl in chow and 1% NaCl in water) right from weaning period (3-week after birth) for 1–3 months. Results: Behavioral analysis demonstrated that HSD-fed mice were hypersensitive to mechanical stimuli. Moreover, HSD induced an expansion of circulating monocytes, especially the proinflammatory monocyte (Ly6Chigh, CCR2+) subsets. HSD also increased the density of Iba-1+ microglia and the number of FcγII/III receptor (CD16/32) expressing cells in the lumbar spinal cord. Prolonged HSD feeding, meanwhile, resulted in increased infiltration of monocyte to the peripheral nerves, contributing to the monocyte-derived macrophage (CD11b+, F4/80+) population. Finally, shifting the HSD back to the regular laboratory chow (with 0.3% NaCl) cannot reverse the HSD-induced mechanical hypersensitivity myeloid cell expansion and polarization towards the inflammatory subsets in the periphery. However, treating HSD mice with CCR2 antagonist effectively normalized the pain threshold and myeloid cell profile in the peripheral blood and nerves. Discussion/Conclusions: Long term HSD feeding decreased mouse mechanical thresholds, in parallel with an expansion and polarization of myeloid cells towards inflammatory status. Such changes were not reversible when HSD-fed mice back to normal diet. However, blocking CCR2 signaling successfully attenuated HSD-induced hypersensitivity.

Convulsive status epilepticus (CSE) is the most serious seizure type in status epilepticus (SE), which may cause irreversible damage of brain and other vital organs without prompt and effective treatment, and result in a high mortality. Therefore, effective pre-hospital drug therapy can ensure the success of treatment for CSE. DOI: 10.3969/j.issn.1672-6731.2015.11.004

Temporomandibular disorder (TMD) is a set of heterogeneous musculoskeletal conditions involving the temporomandibular joint (TMJ) and/or the masticatory muscles. Up to 33% of the population has had at least 1 symptom of TMD with 5% to 10% of them requiring treatment. Common symptoms include limited jaw movement, joint sound, and pain in the orofacial area. Once TMD becomes chronic, it can be debilitating with comorbidities that greatly reduce one's overall quality of life. However, the underlying mechanism of TMD is unclear because of the multicausative nature of the disease. Here, we report a novel mouse model of TMD where a bite block was placed in between the upper and lower incisors such that the mouth was kept maximally open for 1.5 hours per day for 5 days. After sustained mouth opening, mice developed persistent orofacial mechanical allodynia and TMJ dysfunction. At the cellular level, we found masseter muscle dystrophy, and increased proteoglycan deposition and hypertrophic chondrocytes in the mandibular condyle. Increased F4/80 macrophages were also observed in the masseter muscles and the TMJ posterior synovium. We also found ATF3 neuronal injury and increased F4/80 macrophages in the trigeminal ganglia. Microglia activation was observed in the trigeminal subnucleus caudalis. Inhibiting macrophage and microglia activation with a colony stimulating factor-1 receptor inhibitor prevented the development of orofacial mechanical allodynia, but not TMJ dysfunction. This study suggests that mouth opening for an extended period during dental treatments or oral intubations may risk the development of chronic TMD and inflammation associated with macrophage and microglia in the tissue and trigeminal system contributes to the development of TMD pain. [ABSTRACT FROM AUTHOR]

Introduction: Neuropathic pain is a debilitating condition. The importance of neuroimmune interactions in neuropathic pain has been evidenced by the involvement of different immune cells in peripheral and central sensitization of pathological pain. Macrophages and microglia are the most abundant immune cells activated in injured nerves and spinal cord, respectively. Several lines of evidence showed that macrophage/microglia survival, activation, proliferation, and differentiation require the involvement of macrophage-colony stimulating factor. In this study, we investigated whether blocking macrophage-colony stimulating factor/colony stimulating factor 1 receptor signaling can be effective in relieving neuropathic pain. Materials and methods: Partial sciatic nerve ligation was performed in mice to induce neuropathic pain behavior. Mice were orally treated with a selective colony stimulating factor 1 receptor inhibitor, PLX5622, daily in both preventive (two days prior to surgery until D14 post-partial sciatic nerve ligation) and reversal paradigms (D28-D33 post-partial sciatic nerve ligation). Animal neuropathic pain behavior was monitored using von Frey hairs and acetone application. Phenotype of macrophages in injured nerves was analyzed at D3 and D33 post-injury using flow cytometry analysis. The effect of PLX5622 on microglia activation in lumbar spinal cord was further examined by immunohistochemistry using Iba-1 antibody. Results: Significant alleviation of both mechanical and cold allodynia was observed in PLX5622-treated animals, both in preventive and reversal paradigms. PLX5622 treatment reduced the total number of macrophages in injured nerves, it appears colony stimulating factor 1 receptor inhibition affected more specifically CD86+ (M1 like) macrophages. Consequently, the expression of various pro-inflammatory cytokines (TNF-α, IL-1β) was reduced. Microglia activation in dorsal horn of lumbar spinal cord following partial sciatic nerve ligation was significantly inhibited with PLX5622 treatment in both preventive and reversal paradigms. Conclusion: Macrophages in peripheral nerve and microglia in the spinal cord are required in the generation and maintenance of injury-associated neuropathic pain. Blocking macrophage-colony stimulating factor/colony stimulating factor 1 receptor signaling on these myeloid cells along the pain transmission pathway is an effective strategy to alleviate neuropathic pain. [ABSTRACT FROM AUTHOR]

While spinal microglia play a role in early stages of neuropathic pain etiology, whether they are useful targets to reverse chronic pain at late stages remains unknown. Here, we show that microglia activation in the spinal cord persists for >3 months following nerve injury in rodents, beyond involvement of proinflammatory cytokine and chemokine signalling. In this chronic phase, selective depletion of spinal microglia in male rats with the targeted immunotoxin Mac1-saporin and blockade of brain-derived neurotrophic factor-TrkB signalling with intrathecal TrkB Fc chimera, but not cytokine inhibition, almost completely reversed pain hypersensitivity. By contrast, local spinal administration of Mac1-saporin did not affect nociceptive withdrawal threshold in control animals nor did it affect the strength of afferent-evoked synaptic activity in the spinal dorsal horn in normal conditions. These findings show that the long-term, chronic phase of nerve injury-induced pain hypersensitivity is maintained by microglia-neuron interactions. The findings also effectively separate the central signalling pathways underlying the maintenance phase of the pathology from the early and peripheral inflammatory reactions to injury, pointing to different targets for the treatment of acute vs chronic injury-induced pain. [ABSTRACT FROM AUTHOR]

Autoimmune peripheral neuropathies such as Guillain-Barre Syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) affect millions of people worldwide. Despite significant advances in understanding the pathology, the molecular and cellular mechanisms of immune-mediated neuropathies remain elusive. T lymphocytes definitely play an important role in disease pathogenesis and CD4+ T cells have been the main area of research for decades. This is partly due to the fact that the most frequent animal model to study autoimmune peripheral neuropathy is experimental allergic neuritis (EAN). As it is induced commonly by immunization with peripheral nerve proteins, EAN is driven mainly by CD4+ T cells. However, similarly to what has been reported for patients suffering from multiple sclerosis, a significant body of evidence indicates that CD8+ T cells may play a pathogenic role in GBS and CIDP disease development and/or progression. Here, we summarize clinical studies pertaining to the presence and potential role of CD8+ T cells in autoimmune peripheral neuropathies. We also discuss the findings from our most recent studies using a transgenic mouse line (L31 mice) in which the T cell co-stimulator molecule B7.2 (CD86) is constitutively expressed in antigen presenting cells of the nervous tissues. L31 mice spontaneously develop peripheral neuropathy, and CD8+ T cells are found accumulating in peripheral nerves of symptomatic animals. Interestingly, depletion of CD4+ T cells accelerates disease onset and increases disease prevalence. Finally, we point out some unanswered questions for future research to dissect the critical roles of CD8+ T cells in autoimmune peripheral neuropathies. [ABSTRACT FROM AUTHOR]

Peripheral nerve lesion triggers alterations in the spinal microenvironment that contribute to the pathogenesis of neuropathic pain. While neurons and glia have been implicated in these functional changes, it remains largely underexplored whether the blood-spinal cord barrier (BSCB) is also involved. The BSCB is an important component in the CNS homeostasis, and compromised BSCB has been associated with different pathologies affecting the spinal cord. Here, we demonstrated that a remote injury on the peripheral nerve in rats triggered a leakage of the BSCB, which was independent of spinal microglial activation. The increase of BSCB permeability to different size tracers, such as Evans Blue and sodium fluorescein, was restricted to the lumbar spinal cord and prominent for at least 4 weeks after injury. The spinal inflammatory reaction triggered by nerve injury was a key player in modulating BSCB permeability. We identified MCP-1 as an endogenous trigger for the BSCB leakage. BSCB permeability can also be impaired by circulating IL-1β. In contrast, antiinflammatory cytokines TGF-β1 and IL-10 were able to shut down the openings of the BSCB following nerve injury. Peripheral nerve injury caused a decrease in tight junction and caveolae-associated proteins. Interestingly, ZO-1 and occludin, but not caveolin-1, were rescued by TGF-β1. Furthermore, our data provide direct evidence that disrupted BSCB following nerve injury contributed to the influx of inflammatory mediators and the recruitment of spinal blood borne monocytes/macrophages, which played a major role in the development of neuropathic pain. These findings highlight the importance of inflammation in BSCB integrity and in spinal cord homeostasis. [ABSTRACT FROM AUTHOR]

Background: Understanding the underlying mechanisms of neuropathic pain caused by damage to the peripheral nervous system remains challenging and could lead to significantly improved therapies. Disturbance of homeostasis not only occurs at the site of injury but also extends to the spinal cord and brain involving various types of cells. Emerging data implicate neuroimmune interaction in the initiation and maintenance of chronic pain hypersensitivity. Results: In this study, we sought to investigate the effects of TGF-β1, a potent anti-inflammatory cytokine, in alleviating nerve injury-induced neuropathic pain in rats. By using a well established neuropathic pain animal model (partial ligation of the sciatic nerve), we demonstrated that intrathecal infusion of recombinant TGF-β1 significantly attenuated nerve injury-induced neuropathic pain. TGF-β1 treatment not only prevents development of neuropathic pain following nerve injury, but also reverses previously established neuropathic pain conditions. The biological outcomes of TGF-β1 in this context are attributed to its pleiotropic effects. It inhibits peripheral nerve injury-induced spinal microgliosis, spinal microglial and astrocytic activation, and exhibits a powerful neuroprotective effect by preventing the induction of ATF3+ neurons following nerve ligation, consequently reducing the expression of chemokine MCP-1 in damaged neurons. TGF-β1 treatment also suppresses nerve injury-induced inflammatory response in the spinal cord, as revealed by a reduction in cytokine expression. Conclusion: Our findings revealed that TGF-β1 is effective in the treatment of neuropathic by targeting both neurons and glial cells. We suggest that therapeutic agents such as TGF-β1 having multipotent effects on different types of cells could work in synergy to regain homeostasis in local spinal cord microenvironments, therefore contributing to attenuate neuropathic pain. [ABSTRACT FROM AUTHOR]

Neuropathic pain resulting from damage to or dysfunction of peripheral nerves is not well understood and difficult to treat. Although CNS hyperexcitability is a critical component, recent findings challenge the neuron-centric view of neuropathic pain etiology and pathology. Indeed, glial cells were shown to play an active role in the initiation and maintenance of pain hypersensitivity. However, the origins of these cells and the triggers that induce their activation have yet to be elucidated. Here we show that, after peripheral nerve injury induced by a partial ligation on the sciatic nerve, in addition to activation of microglia resident to the CNS, hematogenous macrophage/monocyte infiltrate the spinal cord, proliferate, and differentiate into microglia. Signaling from chemokine monocyte chemoattractant protein-1 (MCP-1, CCL2) to its receptor CCR2 is critical in the spinal microglial activation. Indeed, intrathecal injection of MCP-1 caused activation of microglia in wild-type but not in CCR2-deficient mice. Furthermore, treatment with an MCP-1 neutralizing antibody prevented bone marrow-derived microglia (BMDM) infiltration into the spinal cord after nerve injury. In addition, using selective knock-out of CCR2 in resident microglia or BMDM, we found that, although total CCR2 knock-out mice did not develop microglial activation or mechanical allodynia, CCR2 expression in either resident microglia or BMDM is sufficient for the development of mechanical allodynia. Thus, to effectively relieve neuropathic pain, both CNS resident microglia and blood-borne macrophages need to be targeted. These findings also open the door for a novel therapeutic strategy: to take advantage of the natural ability of bone marrow-derived cells to infiltrate selectively affected CNS regions by using these cells as vehicle for targeted drug delivery to inhibit hypersensitivity and chronic pain. [ABSTRACT FROM AUTHOR]

Abstract Parkinson’s disease (PD) and Parkinsonism are common neurodegenerative disorders with continuously increasing prevalence, causing high global burdens. However, data concerning the comorbidity burden of patients with PD or Parkinsonism in China are lacking. To investigate the health condition and comorbidity burden, a total of 3367 PD and 823 Parkinsonism patients were included from seven tertiary hospitals in seven cities across China from 2003 to 2012. Their comorbidity burden was collected and quantified by the Elixhauser Comorbidity Index (ECI) and Charlson Comorbidity Index (CCI). The comorbidity spectra differed between PD and Parkinsonism patients. Compared with PD patients, Parkinsonism patients were older (69.8 ± 11.5 vs. 67.9 ± 11.4, P

Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer′s disease patients. This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B (NR2B) expression. An APP695V7171 transgenic mouse model of Alzheimer′s disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically. Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2B receptors and Fyn expression. It also reversed parameters for synaptic interface structure of gray type I. These findings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain, and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer′s disease.