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Cerebral Production and Action of Pro-inflammatory Cytokines

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (30 July 2021) | Viewed by 45565

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Dr. Jan-Pieter Konsman

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CNRS UMR 5287 Institute for Cognitive and Integrative Neurosciences in Aquitaine (INCIA), University of Bordeaux, 33076 Bordeaux, France
Interests: blood-brain interface; cytokine; food intake; inflammation; sickness behavior
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to better understand cytokine production and action in the brain beyond their involvement in local immune responses to an insult or infection of the central nervous system (CNS). One domain in which research into brain cytokine production and action has been particularly active over the past few decades is that aiming to explain the occurrence of nonspecific disease symptoms involving CNS-regulated physiology and behavior, such as fever, increased sleep, and reduced food intake, after the systemic detection of bacterial fragments. Another domain of research addressing the role of brain cytokine production and action concerns the regulation of some important biological functions like sleep and energy balance.

While the majority of the work on brain cytokine production and action has historically been on pro-inflammatory cytokines such as interleukin-1, it is important to realize that cytokines comprise many different biologically-active molecules and include interferons, interleukins, and chemokines, but also adipokines, such as leptin. Thus, several new perspectives have arisen on cytokine brain production and action that surpass the domain of classic neuroimmunology and seem closer in spirit to integrative physiology and behavior. These new perspectives can be expected to give rise to new potential therapeutic avenues of pharmacological intervention strategies.

This Special Issue may include manuscripts on the role of brain cytokine production and action in relation to brain networks (neuronal and non-neuronal) involved in physiology, behavior, emotion, and cognition in health and disease beyond their action in mediating cellular responses to local injury or infection of the CNS. We thus welcome papers reporting new experimental research or methods, clinical studies and trials, and reviews with original theoretical perspectives from international researchers and clinicians.

Dr. Jan-Pieter Konsman
Guest Editor

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Keywords

behavior
brain
CNS expression
cytokine
energy balance
health and disease
physiology
sleep

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Published Papers (10 papers)

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Research

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15 pages, 2316 KiB

Open AccessArticle

Old and New Biomarkers for Infection, Inflammation, and Autoimmunity in Treatment-Resistant Affective and Schizophrenic Spectrum Disorders

by Christian Scheiber, Tanja Schulz, Julian M. Schneider, Karl Bechter and E. Marion Schneider

Pharmaceuticals 2022, 15(3), 299; https://doi.org/10.3390/ph15030299 - 28 Feb 2022

Cited by 8 | Viewed by 3344

Abstract

Affective (AF) and Schizophrenic (SZ) Spectrum disorders manifest with risk factors, involving inflammatory processes linked to infections and autoimmunity. This study searched for novel biomarkers in cerebrospinal fluid (CSF) and peripheral blood. A total of 29 AF and 39 SZ patients with treatment-resistant disease were included. In CSF, the chemokine IL-8 was significantly elevated in AF and SZ patients. IL-8 promotes chemotaxis by neutrophils and may originate from different tissues. S100B, a glia-derived brain damage marker, was higher in CSF from AF than SZ patients. Among the plasma-derived biomarkers, ferritin was elevated in AF and SZ. Soluble CD25, indicating T_reg dysfunction, was higher in SZ than in AF patients. Interferon-γ, implying virus-specific immune activation, was positive in selective AF patients, only. Both groups showed elevated expression of immunosuppressive CD33 on monocytes, but higher amounts of CD123⁺ plasmacytoid dendritic cells were restricted to SZ. In conclusion, chemotactic IL-8 indicates neuronal stress and inflammation in the CSF of both groups. Novel plasma-derived biomarkers such as sCD25 and monocytic CD33 distinguish SZ from AF with an autoimmune phenotype. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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13 pages, 1054 KiB

Open AccessArticle

Brain Perivascular Macrophages Do Not Mediate Interleukin-1-Induced Sickness Behavior in Rats

by Léa Chaskiel, Robert Dantzer and Jan Pieter Konsman

Pharmaceuticals 2021, 14(10), 1030; https://doi.org/10.3390/ph14101030 - 11 Oct 2021

Cited by 4 | Viewed by 2369

Abstract

Sickness behavior, characterized by on overall reduction in behavioral activity, is commonly observed after bacterial infection. Sickness behavior can also be induced by the peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1β), a pro-inflammatory cytokine released by LPS-activated macrophages. In addition to the microglia, the brain contains perivascular macrophages, which express the IL-1 type 1 receptor (IL-1R1). In the present study, we assessed the role of brain perivascular macrophages in mediating IL-1β-induced sickness behavior in rats. To do so, we used intracerebroventricular (icv) administration of an IL-1β-saporin conjugate, known to eliminate IL-R1-expressing brain cells, prior to systemic or central IL-1β injection. Icv IL-1β-saporin administration resulted in a reduction in brain perivascular macrophages, without altering subsequent icv or ip IL-1β-induced reductions in food intake, locomotor activity, and social interactions. In conclusion, the present work shows that icv IL-1β-saporin administration is an efficient way to target brain perivascular macrophages, and to determine whether these cells are involved in IL-1β-induced sickness behavior. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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20 pages, 6309 KiB

Open AccessArticle

Dysregulation of Blood-Brain Barrier and Exacerbated Inflammatory Response in Cx47-Deficient Mice after Induction of EAE

by Filippos Stavropoulos, Elena Georgiou, Irene Sargiannidou and Kleopas A. Kleopa

Pharmaceuticals 2021, 14(7), 621; https://doi.org/10.3390/ph14070621 - 28 Jun 2021

Cited by 17 | Viewed by 3825

Abstract

Induction of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), in connexin 32 (Cx32) or Cx47 knockout (KO) mice with deficiency in oligodendrocyte gap junctions (GJs) results in a more severe disease course. In particular, Cx47 KO EAE mice experience an earlier EAE onset and more pronounced disease severity, accompanied by dysregulated pro-inflammatory responses preceding the disease manifestations. In this study, analysis of relevant pro-inflammatory cytokines in wild type EAE, Cx32 KO EAE, and Cx47 KO EAE mice revealed altered expression of Vcam-1 preceding EAE [7 days post injection (dpi)], of Ccl2 at the onset of EAE (12 dpi), and of Gm-csf at the peak of EAE (24 dpi) in Cx47 KO EAE mice. Moreover, Cx47 KO EAE mice exhibited more severe blood-spinal cord barrier (BSCB) disruption, enhanced astrogliosis with defects in tight junction formation at the glia limitans, and increased T-cell infiltration prior to disease onset. Thus, Cx47 deficiency appears to cause dysregulation of the inflammatory profile and BSCB integrity, promoting early astrocyte responses in Cx47 KO EAE mice that lead to a more severe EAE outcome. Further investigation into the role of oligodendrocytic Cx47 in EAE and multiple sclerosis pathology is warranted. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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28 pages, 2414 KiB

Open AccessArticle

LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein

by Verena Peek, Lois M. Harden, Jelena Damm, Ferial Aslani, Stephan Leisengang, Joachim Roth, Rüdiger Gerstberger, Marita Meurer, Maren von Köckritz-Blickwede, Sabine Schulz, Bernhard Spengler and Christoph Rummel

Pharmaceuticals 2021, 14(6), 558; https://doi.org/10.3390/ph14060558 - 11 Jun 2021

Cited by 12 | Viewed by 4232

Abstract

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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15 pages, 3336 KiB

Open AccessArticle

Distinct Modulatory Effects of Fever-Range Hyperthermia on the Response of Breast Cancer Cells and Macrophages to Mistletoe (Viscum album L.) Extract

by Henryk M. Kozłowski, Małgorzata Pawlikowska, Justyna Sobocińska, Tomasz Jędrzejewski, Artur Dzialuk and Sylwia Wrotek

Pharmaceuticals 2021, 14(6), 551; https://doi.org/10.3390/ph14060551 - 8 Jun 2021

Cited by 3 | Viewed by 2878

Abstract

Heat utility as a critical component of fever is often ignored, although the symptom is observed in many medical conditions. Mistletoe extract (ME) is an adjunctive medication prescribed to cancer patients. The increase in body temperature is frequently observed in patients following ME administration. Nevertheless, the impact of this fever on the effectiveness of therapy is unknown. Therefore, we aimed to investigate the effect of fever-range temperatures on ME-treated breast cancer cells and macrophages. The cells were simultaneously stimulated with ME and subjected to fever-range hyperthermia (FRH; 39 °C or 41 °C). After co-treatment, the cell viability, generation of reactive oxygen species (ROS), cell cycle distribution, and production of pro-inflammatory factors (interleukin (IL)-1β, IL-6, and cyclooxygenase (COX)-2) were evaluated. The results showed that the exposure of ME-treated breast cancer cells to FRH at 39 °C resulted in a slight decrease in their viability, whereas FRH of 41 °C enhanced this effect. Only FRH of 41 °C induced minor changes in ROS level in ME-treated breast cancer cell lines. In ME-treated macrophages, FRH stimulated cell proliferation. The cell cycle distribution analysis showed a difference between cells cultured at 39 °C and 41 °C in all examined cell lines. Moreover, hyperthermia at 41 °C completely inhibited the ME-induced increase in IL-1β and IL-6 expression in MCF-7 breast cancer cells, whereas this effect was not observed in 4T1 breast cancer cells. In contrast, in ME-treated macrophages, FRH of 41 °C strongly up-regulated expression of the pro-inflammatory factors. We conclude that fever is an important component of ME therapy that differentially affects cancer and immune cells. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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13 pages, 2376 KiB

Open AccessArticle

Sample Preparation Strategies for Antibody-Free Quantitative Analysis of High Mobility Group Box 1 Protein

by Ingeborg Kvivik, Grete Jonsson, Roald Omdal and Cato Brede

Pharmaceuticals 2021, 14(6), 537; https://doi.org/10.3390/ph14060537 - 3 Jun 2021

Cited by 2 | Viewed by 3158

Abstract

Sickness behavior and fatigue are induced by cerebral mechanisms involving inflammatory cytokines. High mobility group box 1 (HMGB1) is an alarmin, and a potential key player in this process. Reliable quantification methods for total HMGB1 and its redox variants must be established in order to clearly understand how it functions. Current methods pose significant challenges due to interference from other plasma proteins and autoantibodies. We aimed to develop an antibody-free sample preparation method followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to measure HMGB1 in human plasma. Different methods were applied for the removal of interfering proteins and the enrichment of HMGB1 from spiked human plasma samples. A comparison of methods showed an overall low extraction recovery (<40%), probably due to the stickiness of HMGB1. Reversed-phase liquid chromatography separation of intact proteins in diluted plasma yielded the most promising results. The method produced an even higher degree of HMGB1 purification than that observed with immunoaffinity extraction. Detection sensitivity needs to be further improved for the measurement of HMGB1 in patient samples. Nevertheless, it has been demonstrated that a versatile and fully antibody-free sample preparation method is possible, which could be of great use in further investigations. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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Review

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14 pages, 323 KiB

Open AccessEditor’s ChoiceReview

Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!

by Jan Pieter Konsman

Pharmaceuticals 2022, 15(2), 140; https://doi.org/10.3390/ph15020140 - 25 Jan 2022

Cited by 33 | Viewed by 6547

Abstract

In spite of the brain-protecting tissues of the skull, meninges, and blood-brain barrier, some forms of injury to or infection of the CNS can give rise to cerebral cytokine production and action and result in drastic changes in brain function and behavior. Interestingly, peripheral infection-induced systemic inflammation can also be accompanied by increased cerebral cytokine production. Furthermore, it has been recently proposed that some forms of psychological stress may have similar CNS effects. Different conditions of cerebral cytokine production and action will be reviewed here against the background of neuroinflammation. Within this context, it is important to both deepen our understanding along already taken paths as well as to explore new ways in which neural functioning can be modified by cytokines. This, in turn, should enable us to put forward different modes of cerebral cytokine production and action in relation to distinct forms of neuroinflammation. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

22 pages, 1370 KiB

Open AccessReview

Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

by Carolina Araújo Moraes, Camila Zaverucha-do-Valle, Renaud Fleurance, Tarek Sharshar, Fernando Augusto Bozza and Joana Costa d’Avila

Pharmaceuticals 2021, 14(5), 416; https://doi.org/10.3390/ph14050416 - 1 May 2021

Cited by 43 | Viewed by 5571

Abstract

Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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20 pages, 1914 KiB

Open AccessReview

Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders

by Karen Bohmwald, Catalina A. Andrade and Alexis M. Kalergis

Pharmaceuticals 2021, 14(4), 340; https://doi.org/10.3390/ph14040340 - 8 Apr 2021

Cited by 15 | Viewed by 5465

Abstract

Neurobehavioral alterations and cognitive impairment are common phenomena that represent neuropsychiatric disorders and can be triggered by an exacerbated immune response against pathogens, brain injury, or autoimmune diseases. Pro-inflammatory molecules, such as cytokines and chemokines, are produced in the brain by resident cells, mainly by microglia and astrocytes. Brain infiltrating immune cells constitutes another source of these molecules, contributing to an impaired neurological synapse function, affecting typical neurobehavioral and cognitive performance. Currently, there is increasing evidence supporting the notion that behavioral alterations and cognitive impairment can be associated with respiratory viral infections, such as human respiratory syncytial virus, influenza, and SARS-COV-2, which are responsible for endemic, epidemic, or pandemic outbreak mainly in the winter season. This article will review the brain′s pro-inflammatory response due to infection by three highly contagious respiratory viruses that are the leading cause of acute respiratory illness, morbidity, and mobility in infants, immunocompromised and elderly population. How these respiratory viral pathogens induce increased secretion of pro-inflammatory molecules and their relationship with the alterations at a behavioral and cognitive level will be discussed. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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17 pages, 627 KiB

Open AccessReview

CCL-11 or Eotaxin-1: An Immune Marker for Ageing and Accelerated Ageing in Neuro-Psychiatric Disorders

by Mariya Ivanovska, Zakee Abdi, Marianna Murdjeva, Danielle Macedo, Annabel Maes and Michael Maes

Pharmaceuticals 2020, 13(9), 230; https://doi.org/10.3390/ph13090230 - 2 Sep 2020

Cited by 57 | Viewed by 7157

Abstract

Background: CCL-11 (eotaxin) is a chemokine with an important role in allergic conditions. Recent evidence indicates that CCL-11 plays a role in brain disorders as well. This paper reviews the associations between CCL-11 and aging, neurodegenerative, neuroinflammatory and neuropsychiatric disorders. Methods: Electronic databases were searched for original articles examining CCL-11 in neuropsychiatric disorders. Results: CCL-11 is rapidly transported from the blood to the brain through the blood-brain barrier. Age-related increases in CCL-11 are associated with cognitive impairments in executive functions and episodic and semantic memory, and therefore, this chemokine has been described as an “Endogenous Cognition Deteriorating Chemokine” (ECDC) or “Accelerated Brain-Aging Chemokine” (ABAC). In schizophrenia, increased CCL-11 is not only associated with impairments in cognitive functions, but also with key symptoms including formal thought disorders. Some patients with mood disorders and premenstrual syndrome show increased plasma CCL-11 levels. In diseases of old age, CCL-11 is associated with lowered neurogenesis and neurodegenerative processes, and as a consequence, increased CCL-11 increases risk towards Alzheimer’s disease. Polymorphisms in the CCL-11 gene are associated with stroke. Increased CCL-11 also plays a role in neuroinflammatory disease including multiple sclerosis. In animal models, neutralization of CCL-11 may protect against nigrostriatal neurodegeneration. Increased production of CCL-11 may be attenuated by glucocorticoids, minocycline, resveratrol and anti-CCL11 antibodies. Conclusions: Increased CCL-11 production during inflammatory conditions may play a role in human disease including age-related cognitive decline, schizophrenia, mood disorders and neurodegenerative disorders. Increased CCL-11 production is a new drug target in the treatment and prevention of those disorders. Full article

(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

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