Peripheral Inflammatory Processes Research Articles

Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications.

Neuroinflammation appears to be an important pathogenic process in amyotrophic lateral sclerosis (ALS). Dysfunction of central immune pathways, including activation of microglia and astrocytes, and peripherally derived immune cells, initiate noncell autonomous inflammatory mechanisms leading to degeneration. Cell autonomous pathways linked to ALS genetic mutations have been recently identified as contributing mechanism for neurodegeneration. The current review provides insights into the pathogenic importance of central and peripheral inflammatory processes in ALS pathogenesis and appraises their potential as therapeutic targets. ALS is a multistep process mediated by a complex interaction of genetic, epigenetic, and environmental factors. Noncell autonomous inflammatory pathways contribute to neurodegeneration in ALS. Activation of microglia and astrocytes, along with central nervous system infiltration of peripherally derived pro-inflammatory innate (NK-cells/monocytes) and adaptive (cell-mediated/humoral) immune cells, are characteristic of ALS. Dysfunction of regulatory T-cells, elevation of pro-inflammatory cytokines and dysbiosis of gut microbiome towards a pro-inflammatory phenotype, have been reported as pathogenic mechanisms in ALS. Dysregulation of adaptive and innate immunity is pathogenic in ALS, being associated with greater disease burden, more rapid disease course and reduced survival. Strategies aimed at modulating the pro-inflammatory immune components could be of therapeutic utility.

Does retinal microglia respond to peripheral nervous system injury?

The nervous system is the principal integration and coordination centre of the organism receiving, processing and transmitting information to produce a response that regulates and maintains homeostasis. In the central nervous system (CNS), homeostasis is regulated by haemato‐neuronal barriers that prevent free entry to immune system cells, although there is increasing evidence that neuro‐immunological interactions during injury, inflammation and chronic peripheral disease may contribute to the establishment and development of chronic neurodegenerative pathologies at the CNS level.Inflammation plays a significant role in the resolution and sequelae of CNS damage. In recent years, special attention has been dedicated to the role and phenotype of phagocytic cells acting in the CNS and, in particular, to the study of which macrophage subpopulations contribute to excessive or detrimental inflammation or, on the contrary, to beneficial repair or resolution of the lesion.All this raises the question of how local peripheral neuroimmunological interaction induces an inflammatory response in the CNS and how this can be better understood. The study of this phenomenon in the retina is of particular interest, as the retina does not receive neural afferents from other areas of the CNS.The use of experimental models of peripheral lesions of the peripheral nervous system, such as sciatic nerve trauma, or inflammatory lesions, such as the induction of a peripheral arthritic joint process, aims to investigate the time course of the response in the CNS to local peripheral inflammation in the retina of adult mice. The results reveal qualitative and quantitative cellular changes compatible with microglial activation processes in the retina, but no significant changes occur in its neuronal population. The presence and activation of haematic mononuclear‐phagocytic cells of myelopoietic origin are also observed in the retina, where they differentiate into microglia.In the absence of local retinal injury, we postulate that the detected neuroinflammatory reaction may be due to a preventive CNS defence reaction favouring neuroprotection since microglial cells derived from the haematic monocyte/macrophage cell population may consider within the M2 macrophage subtype, characterized by their ability to suppress proinflammatory immune responses and promote the expression of neuroprotective and repair genes.On the other hand, we must consider that activation of the mononuclear phagocytic system in the retina caused by a peripheral inflammatory process could potentially be detrimental to patients with neurodegenerative retinal diseases or contribute to their development.

Association between plasma inflammatory biomarkers and [18F]FDG‐PET signal in a transgenic amyloid rat model

AbstractBackgroundNeuroinflammation is thought to play an important role in the pathogenesis of Alzheimer’s disease (AD). It has recently been demonstrated that [18F]FDG positron emission tomography (PET) signal is sensitive to central inflammatory changes in AD. However, it is unknown whether blood cytokines, which are important signaling molecules that regulate the peripheral inflammatory process, are associated with the cerebral [18F]FDG‐PET signal. In this work, we aimed to investigate whether plasma cytokines are associated with brain glucose metabolism in a transgenic amyloid rat model.MethodBrain metabolism of 4‐ and 10‐month‐old wild‐type (WT) and APP/PS1 rats (TgF344‐AD) were assessed with [18F]FDG‐PET imaging. Plasma inflammatory markers (IFN‐γ, IL‐1α, IL‐1β, IL‐6, IL‐10 and TNF‐α) were measured by multiplex immunoassay. [18F]FDG‐SUVr was calculated with pons as the reference region. Correlation between inflammatory markers and [18F]FDG‐PET signal was conducted at the voxel level (RMINC; p<0.05 and t>2).ResultAt 4 months, IL‐10 levels significantly associate with [18F]FDG‐PET signal in the frontal and temporoparietal cortices (FCx and TPCx) and hippocampus (Fig1A), whereas other biomarkers present only small clusters associated with [18F]FDG‐PET signal (Fig1A). At 10 months, a positive association with [18F]FDG‐PET was found between IL‐1α and IL‐1β at FCx and TPCx, while IL‐10 showed a positive correlation at the TPCx (Fig1B). Additionality, IFN‐γ and TNF‐α presented small correlation clusters at the TPCx, and IL‐6 at the TPCx and CxF (Fig1B).ConclusionAt the pre‐amyloid plaque stage, only an anti‐inflammatory cytokine, IL‐10, presented positive associations with brain glucose metabolism. However, multiple pro‐inflammatory cytokines correlated with brain glucose metabolism at the amyloid plaque stage. These findings suggest a dual peripheral inflammatory response impacting brain metabolism, which can be associated with amyloid species and deposition.

Tetrandrine attenuates SNI-induced mechanical allodynia by inhibiting spinal CKLF1

Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, possesses anti-inflammatory and immune-modulatory properties. Chemokine-like factor 1 (CKLF1) is known to play a crucial role in both peripheral and central inflammatory processes. This study aimed to investigate the potential anti-NP effects of TET and the involvement of CKLF1 in the action of TET. A male C57BL/6J mice model of NP caused by spared nerve injury (SNI) was established and mechanical withdrawal thresholds were measured using von Frey filaments. The results showed that TET improved mechanical allodynia in SNI mice and the propofol-induced sleep assay demonstrated that the TET group did not exhibit central inhibition, while the pregabalin (PGB) group showed significant central inhibition. Western blotting and immunofluorescence staining showed that TET significantly inhibited spinal protein expression levels of CKLF1, p-NF-κB/NF-κB, p-IKK/IKK, pro-inflammatory cytokines IL-1β and TNF-α, and increased protein expression levels of the anti-inflammatory cytokine IL-10, while inhibiting the expression levels of microglia and astrocyte markers IBA-1 and GFAP of SNI mice. Moreover, immunofluorescence double-labeling results revealed that CKLF1 was predominantly colocalized with microglia of the spinal cord (SC) in SNI mice. C19 (an antagonism peptide of CKLF1) alleviated SNI-induced mechanical pain hypersensitivity, while C27 (an analog peptide of CKLF1) induced mechanical allodynia in normal mice. TET significantly attenuated mechanical allodynia induced by C27 in mice. TET may effectively alleviate NP by reducing neuroinflammation and decreasing CKLF1.

Cell Adhesion Molecules in Schizophrenia Patients with Metabolic Syndrome.

Metabolic syndrome (MetS) is a common comorbidity of schizophrenia and significantly shortens life expectancy of the patients. Intercellular (ICAM), vascular (VCAM), and neural (NCAM) cell adhesion molecules (CAMs) mediate neuroinflammatory processes, and their soluble forms (e.g., sICAM) in plasma are present in parallel with their cell-bound forms. In this study, their serum levels were examined in 211 white Siberian patients with paranoid schizophrenia (82 patients with and 129 without MetS according to the 2005 International Diabetes Federation criteria). Serum levels of CAMs were determined with Magpix and Luminex 200 (Luminex, Austin, TX, USA) using xMAP Technology. The level of sICAM-1 was significantly higher and that of sVCAM-1 significantly lower in patients with MetS compared to patients without MetS. Levels of NCAM did not differ between the groups. More pronounced Spearman's correlations between CAMs, age, duration of schizophrenia, and body-mass index were observed among patients without MetS than among patients with MetS. Our results are consistent with MetS's being associated with endothelial dysfunction along with other components of inflammation. Through these endothelial components of peripheral inflammatory processes, MetS might induce intracerebral neuroinflammatory changes, but further investigation is needed to confirm this.

From Low-Grade Inflammation in Osteoarthritis to Neuropsychiatric Sequelae: A Narrative Review.

Nowadays, osteoarthritis (OA), a common, multifactorial musculoskeletal disease, is considered to have a low-grade inflammatory pathogenetic component. Lately, neuropsychiatric sequelae of the disease have gained recognition. However, a link between the peripheral inflammatory process of OA and the development of neuropsychiatric pathology is not completely understood. In this review, we provide a narrative that explores the development of neuropsychiatric disease in the presence of chronic peripheral low-grade inflammation with a focus on its signaling to the brain. We describe the development of a pro-inflammatory environment in the OA-affected joint. We discuss inflammation-signaling pathways that link the affected joint to the central nervous system, mainly using primary sensory afferents and blood circulation via circumventricular organs and cerebral endothelium. The review describes molecular and cellular changes in the brain, recognized in the presence of chronic peripheral inflammation. In addition, changes in the volume of gray matter and alterations of connectivity important for the assessment of the efficacy of treatment in OA are discussed in the given review. Finally, the narrative considers the importance of the use of neuropsychiatric diagnostic tools for a disease with an inflammatory component in the clinical setting.

Systemic inflammatory markers of persistent cerebral edema after aneurysmal subarachnoid hemorrhage

BackgroundCerebral edema (CE) at admission is a surrogate marker of ‘early brain injury’ (EBI) after subarachnoid hemorrhage (SAH). Only recently has the focus on the changes in CE after SAH such as delayed resolution or newly developed CE been examined. Among several factors, an early systemic inflammatory response has been shown to be associated with CE. We investigate inflammatory markers in subjects with early CE which does not resolve, i.e., persistent CE after SAH.MethodsComputed tomography scans of SAH patients were graded at admission and at 7 days after SAH for CE using the 0–4 ‘subarachnoid hemorrhage early brain edema score’ (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3–5 days [T3] and 6–8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2).ResultsOf the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002–1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE.ConclusionsWe identified serum cytokines at different time points that were independently associated with persistent CE. Specifically, persistent elevations of Eotaxin is associated with persistent CE after SAH.

Hypothalamic Neurochemical Changes in Long-Term Recovered Bilateral Subdiaphragmatic Vagotomized Rats.

BackgroundVagus nerve is one of the crucial routes in communication between the immune and central nervous systems. The impaired vagal nerve function may intensify peripheral inflammatory processes. This effect subsides along with prolonged recovery after permanent nerve injury. One of the results of such compensation is a normalized plasma concentration of stress hormone corticosterone – a marker of hypothalamic-pituitary-adrenal (HPA) axis activity. In this work, we strive to explain this corticosterone normalization by studying the mechanisms responsible for compensation-related neurochemical alterations in the hypothalamus.Materials and MethodsUsing microarrays and high performance liquid chromatography (HPLC), we measured genome-wide gene expression and major amino acid neurotransmitters content in the hypothalamus of bilaterally vagotomized rats, 1 month after surgery.ResultsOur results show that, in the long term, vagotomy affects hypothalamic amino acids concentration but not mRNA expression of tested genes.DiscussionWe propose an alternative pathway of immune to CNS communication after vagotomy, leading to activation of the HPA axis, by influencing central amino acids and subsequent monoaminergic neurotransmission.

Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson´s disease

The role of autoimmunity in neurodegeneration has been increasingly suggested. The renin-angiotensin system (RAS) autoantibodies play a major role in several peripheral inflammatory processes. Dysregulation of brain RAS has been involved in neuroinflammation and neurodegeneration. We aimed to know whether angiotensin type-1 receptor (AT1) autoantibodies (AT1 agonists) and angiotensin-converting enzyme 2 (ACE2) autoantibodies (ACE2 antagonists) may be involved in Parkinson’s disease (PD) progression and constitute a new therapeutical target. Both AT1 and ACE2 serum autoantibodies were higher in a group of 117 PD patients than in a group of 106 controls. Serum AT1 autoantibodies correlated with several cytokines, particularly Tumor Necrosis Factor Ligand Superfamily Member 14 (TNFSF14, LIGHT), and 27-hydroxycholesterol levels. Serum ACE2 autoantibodies correlated with AT1 autoantibodies. Both autoantibodies were found in cerebrospinal fluid (CSF) of four PD patients with CSF samples. Consistent with the observations in patients, experimental dopaminergic degeneration, induced by 6-hydroxydopamine, increased levels of autoantibodies in serum and CSF in rats, as well as LIGHT levels and transglutaminase activity in rat substantia nigra. In cultures, administration of AT1 autoantibodies enhanced dopaminergic neuron degeneration and increased levels of neuroinflammation markers, which was inhibited by the AT1 antagonist candesartan. The results suggest dysregulation of RAS autoantibodies as a new mechanism that can contribute to PD progression. Therapeutical strategies blocking the production, or the effects of these autoantibodies may be useful for PD treatment, and the results further support repurposing AT1 blockers (ARBs) as treatment against PD progression.

Effects of overweight and obesity on cognitive functions of children and adolescents

Recent findings suggest that overweight and obesity in children and adolescents affect cognitive processes and can alter school learning. The so-called executive functions, such as response inhibition capacity, impulsivity control, cognitive flexibility, planning, and decision making, have been inversely related to body mass index. This work aims to examine the neurobiological and psychological hypothesis that explain why overweight, and obesity alter the cognitive functions of children and adolescents. Diets rich in fats and sugars can cause hyperinsulinemia, dyslipidemia, hypertension, augmented abdominal adipose tissue and resistance to insulin and leptin. These metabolic alterations induce a peripheral systemic inflammatory process that can affect the blood-brain barrier and the brain functioning of regions linked to attention and learning and memory processes. Some metabolic disorders of the pregnant mother, obesity during pregnancy and pre- and postnatal traumatic experiences can trigger changes in the control of food intake in children and adolescents and induce overweight in critical stages of their development. Obesity affects the functioning of the hippocampus and produces a decrease in the prefrontal cortex gray matter, thereby modifying cognitive abilities, especially executive functions. Overweight and obesity in childhood and adolescence are a risk factor not only for general health but also for proper brain development and cognitive functions and can therefore lead to school failure.

Peripheral inflammation effects on retinal phagocytic system

AbstractPurposeTo study how a unilateral arthritic inflammatory process, affecting the peripheral nervous system, can activate the mononuclear phagocytic system at retinal level.MethodsAn experimental model of peripheral inflammatory process produced by an intraplantar injection of Freund's complete adjuvant (FCA) in the left hind limb was induced to adult C57BL/6J lysozyme M‐eGFP‐knock‐in (LysM‐eGFP) mice that express LysM‐eGFP selectively in myelomonocytic cells. FCA, sham and naïve mice were processed at different survival times (ranging 1–10 days post‐lesion). Retinas were prepared as whole‐mounts and histologically analyzed for microglia markers and LysM‐eGFP expression.ResultsAfter FCA administration morphological signs compatibles with microglial activation were observed in the eGFP+ cells in the innermost layer of the retina, persisting along the time‐course of study. The three sub‐population of eGFP+ cells identified, amoeboid, ramified and peripheral, showed significant and relevant changes in the distribution pattern respect to that observed in untreated retinas from sham or naïve mice. The quantitative analysis showed statistically significant changes in the expression of eGFP+ and Iba‐1+ for all cell sub‐population in the course of time. However, the number of eGFP+ and Iba‐1 immunonegative amoeboid cells was constant and similar to those of sham or control retinas.ConclusionsInduction of a peripheral inflammatory process by administration of FCA elicits a response from the peripheral bone marrow‐derived monocyte‐macrophage population at retinal level, where these cells are recruited and transformed into microglia.

Acute peripheral inflammation does not change cerebral glucose metabolism

AbstractBackgroundNeuroinflammation is a phenomenon already described in the brain of Alzheimer's disease (AD) individuals, with sustained neuroinflammatory response being detrimental. The effect of peripheral inflammation in AD is less understood. In fact, central nervous system (CNS) is protected from peripheral inflammation by the blood‐brain barrier. However, we recently demonstrated that severe sepsis causes acute brain metabolic disturbances, evidencing the CNS invasion of inflammatory mediators may affect brain function. Nevertheless, whether mild acute peripheral inflammation affects brain metabolism remains unclear. Objective: Here, we aimed at investigating the impact of mild acute peritonitis on brain energetic metabolism. Hypothesis: We hypothesized that mild peripheral inflammation will cause widespread brain glucose hypometabolism.MethodAdult male Wistar rats were randomly separated into carrageenan group, a model of mild acute peripheral inflammation (n=6), and control group (n=6). Peritonitis was induced by the administration of 500 µg of intraperitoneal (i.p.) carrageenan, while the control group was i.p. injected with 500 µl of saline. In vivo cerebral glucose metabolism was assessed using (18F)FDG‐microPET 4 h after inflammatory induction, which represents the first peak of inflammation. The peripheral inflammatory process was evaluated by analyzing the peritoneal lavage in a Flow Cytometer 48 h after the scanning i.p. injections, the second of peak of inflammation,ResultThe animals treated with carrageenan presented a 5‐fold increase in macrophages numbers (p&lt;0,05) and a 2‐fold increase in monocytes numbers (p&gt;0,05). However, our data showed that carrageenan‐induced peripheral inflammation did not cause acute changes in the whole brain glucose metabolism (p&gt;0,05). Further regional analysis, in frontal and temporoparietal cortices, striatum, hippocampus, cerebellum, thalamus and hypothalamus, did not identify any difference between groups.ConclusionMild acute peripheral inflammation does not change brain glucose metabolism. Further evaluation aiming to investigate long‐term consequences of sustained mild inflammation are needed.

Understanding the role of the blood brain barrier and peripheral inflammation on behavior and pathology on ongoing confined cortical lesions

BackgroundInflammation in the Central Nervous System (CNS) is associated with blood brain barrier (BBB) breakdown during the early stages of Multiple Sclerosis (MS), indicating a facilitated entry of waves of inflammatory cells from the circulation to the CNS. In the progressive forms of MS, as the lesion becomes chronic, the inflammation remains trapped within the CNS compartment forming the slow evolving lesion, characterized by low inflammation and microglia activation at the lesions edges. The chronic expression of interleukin 1β (IL-1β) in the cortex induces BBB breakdown, demyelination, neurodegeneration, microglial/macrophage activation and impaired cognitive performance. The latter can be improved, as long as the BBB recovers and the lesion presents low inflammation. Here, we study the effects of peripheral inflammation on cortical central lesions after the restoration of the BBB, in order to elucidate the role of the peripheral inflammation on these lesions with intact BBB, as it occurs in the progressive forms of MS. Materials and methodsCortical lesions and peripheral inflammation were induced by the chronic expression of IL-1β using an adenovector. We performed histological, immunohistochemistry on brain tissue and behavioural analyses. ResultsThe effects of the chronic expression of IL-1β in the cortex resolved within 56 days. However, peripheral and sustained inflammation re-opened the BBB, allowing the reappearance of the neuroinflammatory processes within the cortical lesions, increased demyelination and neurodegeneration, and an increase of the behavioral symptoms, such as cognitive impairment and anxiety-like symptoms. ConclusionsThe early treatment of peripheral inflammatory processes should be considered in order to protect the brain from exacerbation of the ongoing neurodegenerative process.

Gut microbiota modulates the inflammatory response and cognitive impairment induced by sleep deprivation.

Sleep deprivation (SD) is increasingly common in modern society, which can lead to the dysregulation of inflammatory responses and cognitive impairment, but the mechanisms remain unclear. Emerging evidence suggests that gut microbiota plays a critical role in the pathogenesis and development of inflammatory and psychiatric diseases, possibly via gut microbiota-brain interactions and neuroinflammation. The present study investigated the impact of SD on gut microbiota composition and explored whether alterations of the gut microbiota play a causal role in chronic inflammatory states and cognitive impairment that are induced by SD. We found that SD-induced gut dysbiosis, inflammatory responses, and cognitive impairment in humans. Moreover, the absence of the gut microbiota suppressed inflammatory response and cognitive impairment induced by SD in germ-free (GF) mice. Transplantation of the "SD microbiota" into GF mice activated the Toll-like receptor 4/nuclear factor-κB signaling pathway and impaired cognitive function in the recipient mice. Mice that harbored "SD microbiota" also exhibited increases in neuroinflammation and microglial activity in the hippocampus and medial prefrontal cortex. These findings indicate that gut dysbiosis contributes to both peripheral and central inflammatory processes and cognitive deficits that are induced by SD, which may open avenues for potential interventions that can relieve the detrimental consequences of sleep loss.

Pharmacological Strategies to Improve Dendritic Spines in Alzheimer's Disease.

To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.

Involvement of the tuberomammillary nucleus of the hypothalamus in the modulation of nociception and joint edema in a model of monoarthritis

AimsInvestigate the involvement of the histaminergic projections from tuberomammillary nucleus (TMN) to the spinal cord in the modulation of nociception and peripheral edema in a model of monoarthritis. Main methodsSubacute monoarthritis was induced by an intraarticular injection of carrageenan followed by LPS 72 h later. Disability and joint edema were assessed at the 3rd hour after LPS and at every hour up to 6 h. Key findingsIntrathecal administration of histamine potentiated joint incapacitation and edema, while the H1R antagonist cetirizine decreased both. The H3R agonist immepip decreased both incapacitation and edema, while the H3R antagonist thioperamide had the opposite effect. The microinjection of glutamate into the ventral TMN (vTMN) caused an increase of incapacitation and articular edema, whereas the blockade of this nucleus by cobalt chloride inhibited both parameters. Intrathecal administration of cetirizine prevented the increase of incapacitation and joint edema caused by glutamate microinjection into the vTMN. Similarly, an intrathecal injection of the NKCC1 cotransporter inhibitor bumetanide prevented the effects of glutamate microinjection into the vTMN, whereas coadministration of histamine with bumetanide only inhibited the potentiation of joint edema. A microinjection of orexin B into the vTMN potentiated incapacitation and joint edema, while coadministration of the OX1/2 receptor antagonist almorexant with orexin B did not. SignificanceThese data support the notion that TMN participates in the modulation of a peripheral inflammatory process by means of histaminergic projections to the spinal cord, and the hypothalamus may trigger TMN activation by means of glutamate and orexin.

Elevated acute phase proteins reflect peripheral inflammation and disease severity in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem pro-inflammatory neuromuscular disorder compromising muscle function resulting in death. Neuroinflammation is known to accelerate disease progression and accentuate disease severity, but peripheral inflammatory processes are not well documented. Acute phase proteins (APPs), plasma proteins synthesized in the liver, are increased in response to inflammation. The objective of this study was to provide evidence for peripheral inflammation by examining levels of APPs, and their contribution to disease burden and progression rates. Levels of APPs, including soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP), and C-reactive protein (CRP), were elevated in sera, and correlated positively with increased disease burden and faster progression. sCD14 was also elevated in patients’ CSF and urine. After a 3 year follow-up, 72% of the patients with sCD14 levels above the receiver operating characteristics cutoff were deceased whereas only 28% below the cutoff were deceased. Furthermore, disease onset sites were associated with disease progression rates and APP levels. These APPs were not elevated in sera of patients with Alzheimer’s Disease, frontotemporal dementia, or Parkinson’s Disease. These collective APPs accurately reflect disease burden, progression rates, and survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses.

Proinflammatory Extracellular Vesicle-Mediated Signaling Contributes to\xa0the Induction of Neuroinflammation in Animal Models of Endotoxemia and Peripheral Surgical Stress

Peripheral inflammation induced by endotoxemia or surgical stress induces neuroinflammation thereby causing neurological symptoms ranging from sickness behavior to delirium. Thus, proinflammatory signaling must be operative between the periphery and the central nervous system (CNS). In the present study, we tested whether nanometer-sized extracellular vesicles (EVs) that were produced during the peripheral inflammatory process have the capacity to induce neuroinflammation. Conditions of endotoxemia or surgical intervention were simulated in rats by lipopolysaccharide (LPS) injection or partial hepatectomy (HpX). EVs were concentrated from these animals and tested for their proinflammatory action (I) in a microglial cell line and (II) by intracerebroventricular and (III) by intravenous injections into healthy rats. EVs from both conditions induced the secretion of cytokines from the glial cell line. Intracerebroventricular injection of the EVs caused the release of inflammatory cytokines to the cerebrospinal fluid indicating their pro-neuroinflammatory capacity. Finally, proinflammatory EVs were shown to pass the blood–brain barrier and induce neuroinflammation after their intravenous injection. Based on these data, we suggest that EV-associated proinflammatory signaling contributes to the induction of neuroinflammation in endotoxemia and peripheral surgical stress. Preliminary results suggest that peripheral cholinergic signals might be involved in the control of proinflammatory EV-mediated signaling from the periphery to the brain.

The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer's Disease: A Systematic Review.

The evidence of a connection between the peripheral inflammatory processes and neurodegenerative diseases of the central nervous system is becoming more apparent. This review of the related literature highlights the most recent clinical, epidemiological, and in vitro studies trying to investigate possible connections between periodontal bacteria and the onset and progression of Alzheimer’s disease. This review was conducted by searching databases such as PubMed and Scopus using keywords or combinations such as Alzheimer’s Disease AND periodontal or dementia AND periodontitis OR periodontal. After eliminating overlaps and screening the articles not related to these issues, we identified 1088 records and proceeded to the selection of articles for an evaluation of the associative assumptions. The hypothesis suggested by the authors and confirmed by the literature is that the bacterial load and the inflammatory process linked to periodontal disease can intensify inflammation at the level of the central nervous system, favoring the occurrence of the disease. The analysis of the literature highlights how periodontal disease can directly contribute to the peripheral inflammatory environment by the introduction of periodontal or indirect pathogenic bacteria and proinflammatory cytokines locally produced at the periodontal level following bacterial colonization of periodontal defects.

Is there neuroinflammation in depression? Understanding the link between the brain and the peripheral immune system in depression.

Compelling evidence have highlighted the role of inflammation as a possible mechanism linking environmental stress to the development of depression. In particular, the communication between the peripheral and the brain immune system might lead to brain inflammatory processes, in turn causing impaired neurogenesis and neural plasticity. As a consequence, measuring brain inflammation and its possible correlation with peripheral inflammatory processes has become the focus (and a challenge) for a number of recent studies. In this chapter we review the evidence on the link between stress, peripheral and brain inflammation and the way to measure it, through preclinical, post-mortem and clinical models of depression and in healthy humans. We describe the concept of microglial activation as a marker of neuroinflammation and the potential use of anti-inflammatory treatments in depression. The paper concludes by highlighting the unresolved questions and challenges for future studies.