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Editorial

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3 pages, 193 KiB

Open AccessEditorial

Function of Glial Cells in Neuroinflammatory and Neuroimmunological Responses II

by Ruqayya Afridi, Anup Bhusal, Makoto Tsuda, Hoon Ryu and Kyoungho Suk

Cells 2023, 12(13), 1750; https://doi.org/10.3390/cells12131750 - 30 Jun 2023

Viewed by 771

Abstract

It is now well established that glial cells play an equal, if not greater, role in regulating intricate functions of the central nervous system (CNS) compared with neurons [...] Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

Research

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18 pages, 2635 KiB

Open AccessArticle

Intermittent Lead Exposure Induces Behavioral and Cardiovascular Alterations Associated with Neuroinflammation

by Liana Shvachiy, Ângela Amaro-Leal, Tiago F. Outeiro, Isabel Rocha and Vera Geraldes

Cells 2023, 12(5), 818; https://doi.org/10.3390/cells12050818 - 06 Mar 2023

Cited by 5 | Viewed by 1758

Abstract

The nervous system is the primary target for lead exposure and the developing brain appears to be especially susceptible, namely the hippocampus. The mechanisms of lead neurotoxicity remain unclear, but microgliosis and astrogliosis are potential candidates, leading to an inflammatory cascade and interrupting [...] Read more.

The nervous system is the primary target for lead exposure and the developing brain appears to be especially susceptible, namely the hippocampus. The mechanisms of lead neurotoxicity remain unclear, but microgliosis and astrogliosis are potential candidates, leading to an inflammatory cascade and interrupting the pathways involved in hippocampal functions. Moreover, these molecular changes can be impactful as they may contribute to the pathophysiology of behavioral deficits and cardiovascular complications observed in chronic lead exposure. Nevertheless, the health effects and the underlying influence mechanism of intermittent lead exposure in the nervous and cardiovascular systems are still vague. Thus, we used a rat model of intermittent lead exposure to determine the systemic effects of lead and on microglial and astroglial activation in the hippocampal dentate gyrus throughout time. In this study, the intermittent group was exposed to lead from the fetal period until 12 weeks of age, no exposure (tap water) until 20 weeks, and a second exposure from 20 to 28 weeks of age. A control group (without lead exposure) matched in age and sex was used. At 12, 20 and 28 weeks of age, both groups were submitted to a physiological and behavioral evaluation. Behavioral tests were performed for the assessment of anxiety-like behavior and locomotor activity (open-field test), and memory (novel object recognition test). In the physiological evaluation, in an acute experiment, blood pressure, electrocardiogram, and heart and respiratory rates were recorded, and autonomic reflexes were evaluated. The expression of GFAP, Iba-1, NeuN and Synaptophysin in the hippocampal dentate gyrus was assessed. Intermittent lead exposure induced microgliosis and astrogliosis in the hippocampus of rats and changes in behavioral and cardiovascular function. We identified increases in GFAP and Iba1 markers together with presynaptic dysfunction in the hippocampus, concomitant with behavioral changes. This type of exposure produced significant long-term memory dysfunction. Regarding physiological changes, hypertension, tachypnea, baroreceptor reflex impairment and increased chemoreceptor reflex sensitivity were observed. In conclusion, the present study demonstrated the potential of lead intermittent exposure inducing reactive astrogliosis and microgliosis, along with a presynaptic loss that was accompanied by alterations of homeostatic mechanisms. This suggests that chronic neuroinflammation promoted by intermittent lead exposure since fetal period may increase the susceptibility to adverse events in individuals with pre-existing cardiovascular disease and/or in the elderly. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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16 pages, 2528 KiB

Open AccessArticle

Micrandilactone C, a Nortriterpenoid Isolated from Roots of Schisandra chinensis, Ameliorates Huntington’s Disease by Inhibiting Microglial STAT3 Pathways

by Minhee Jang, Jong Hee Choi, Dae Sik Jang and Ik-Hyun Cho

Cells 2023, 12(5), 786; https://doi.org/10.3390/cells12050786 - 02 Mar 2023

Cited by 4 | Viewed by 1519

Abstract

Huntington’s disease (HD) is a neurodegenerative disease that affects the motor control system of the brain. Its pathological mechanism and therapeutic strategies have not been fully elucidated yet. The neuroprotective value of micrandilactone C (MC), a new schiartane nortriterpenoid isolated from the roots [...] Read more.

Huntington’s disease (HD) is a neurodegenerative disease that affects the motor control system of the brain. Its pathological mechanism and therapeutic strategies have not been fully elucidated yet. The neuroprotective value of micrandilactone C (MC), a new schiartane nortriterpenoid isolated from the roots of Schisandra chinensis, is not well-known either. Here, the neuroprotective effects of MC were demonstrated in 3-nitropropionic acid (3-NPA)-treated animal and cell culture models of HD. MC mitigated neurological scores and lethality following 3-NPA treatment, which is associated with decreases in the formation of a lesion area, neuronal death/apoptosis, microglial migration/activation, and mRNA or protein expression of inflammatory mediators in the striatum. MC also inhibited the activation of the signal transducer and activator of transcription 3 (STAT3) in the striatum and microglia after 3-NPA treatment. As expected, decreases in inflammation and STAT3-activation were reproduced in a conditioned medium of lipopolysaccharide-stimulated BV2 cells pretreated with MC. The conditioned medium blocked the reduction in NeuN expression and the enhancement of mutant huntingtin expression in STHdh^Q111/Q111 cells. Taken together, MC might alleviate behavioral dysfunction, striatal degeneration, and immune response by inhibiting microglial STAT3 signaling in animal and cell culture models for HD. Thus, MC may be a potential therapeutic strategy for HD. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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20 pages, 4623 KiB

Open AccessArticle

RIPK1 Regulates Microglial Activation in Lipopolysaccharide-Induced Neuroinflammation and MPTP-Induced Parkinson’s Disease Mouse Models

by Do-Yeon Kim, Yea-Hyun Leem, Jin-Sun Park, Jung-Eun Park, Jae-Min Park, Jihee Lee Kang and Hee-Sun Kim

Cells 2023, 12(3), 417; https://doi.org/10.3390/cells12030417 - 26 Jan 2023

Cited by 9 | Viewed by 2880

Abstract

Increasing evidence suggests a pivotal role of receptor-interacting protein kinase 1 (RIPK1), an initiator of necroptosis, in neuroinflammation. However, the precise role of RIPK1 in microglial activation remains unclear. In the present study, we explored the role of RIPK1 in lipopolysaccharide (LPS)-induced neuroinflammation [...] Read more.

Increasing evidence suggests a pivotal role of receptor-interacting protein kinase 1 (RIPK1), an initiator of necroptosis, in neuroinflammation. However, the precise role of RIPK1 in microglial activation remains unclear. In the present study, we explored the role of RIPK1 in lipopolysaccharide (LPS)-induced neuroinflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice by using RIPK1-specific inhibitors necrostatin-1 (Nec-1) and necrostatin-1 stable (Nec-1s). Nec-1/Nec-1s or RIPK1 siRNA inhibited the production of proinflammatory molecules and the phosphorylation of RIPK1-RIPK3-MLKL and cell death in LPS-induced inflammatory or LPS/QVD/BV6-induced necroptotic conditions of BV2 microglial cells. Detailed mechanistic studies showed that Nec-1/Nec-1s exerted anti-inflammatory effects by modulating AMPK, PI3K/Akt, MAPKs, and NF-κB signaling pathways in LPS-stimulated BV2 cells. Subsequent in vivo studies showed that Nec-1/Nec-1s inhibited microglial activation and proinflammatory gene expression by inhibiting the RIPK1 phosphorylation in the brains of LPS-injected mice. Furthermore, Nec-1/Nec-1s exert neuroprotective and anti-inflammatory effects in MPTP-induced PD mice. We found that p-RIPK1 is mainly expressed in microglia, and thus RIPK1 may contribute to neuroinflammation and subsequent cell death of dopaminergic neurons in MPTP-induced PD model mice. These data suggest that RIPK1 is a key regulator of microglial activation in LPS-induced neuroinflammation and MPTP-induced PD mice. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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11 pages, 3973 KiB

Open AccessArticle

by Anup Bhusal, Youngpyo Nam, Donggun Seo, Won-Ha Lee and Kyoungho Suk

Cells 2022, 11(23), 3886; https://doi.org/10.3390/cells11233886 - 01 Dec 2022

Cited by 2 | Viewed by 1415

Abstract

Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited [...] Read more.

Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited LPS-mediated inflammatory activation of glial cells in culture. In the animal model of LPS-induced neuroinflammation, CRAMP expression was highly induced in multiple cell types, such as astrocytes, microglia, and neurons. Injection of exogenous CRAMP peptide significantly inhibited inflammatory cytokine expression and the reactivity of glial cells in the mouse brain following intraperitoneal or intracerebroventricular LPS administration. Altogether, results of the study suggest that CRAMP plays an important part in containment of LPS-induced neuroinflammatory responses, and that CRAMP can be exploited for the development of targeted therapies for neuroinflammatory conditions associated with bacterial infection. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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Review

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15 pages, 3069 KiB

Open AccessReview

Microglial Responses to Stress-Induced Depression: Causes and Consequences

by Ruqayya Afridi and Kyoungho Suk

Cells 2023, 12(11), 1521; https://doi.org/10.3390/cells12111521 - 31 May 2023

Cited by 9 | Viewed by 2263

Abstract

Chronic stress is a major risk factor for various psychiatric diseases, including depression; it triggers various cellular and structural changes, resulting in the alteration of neurocircuitry and subsequent development of depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of [...] Read more.

Chronic stress is a major risk factor for various psychiatric diseases, including depression; it triggers various cellular and structural changes, resulting in the alteration of neurocircuitry and subsequent development of depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of stress-induced depression revealed microglial inflammatory activation in regions of the brain that regulate mood. Although studies have identified several molecules that trigger inflammatory responses in microglia, the pathways that regulate stress-induced microglial activation remain unclear. Understanding the exact triggers that induce microglial inflammatory activation can help find therapeutic targets in order to treat depression. In the current review, we summarize the recent literature on possible sources of microglial inflammatory activation in animal models of chronic stress-induced depression. In addition, we describe how microglial inflammatory signaling affects neuronal health and causes depressive-like behavior in animal models. Finally, we propose ways to target the microglial inflammatory cascade to treat depressive disorders. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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17 pages, 1500 KiB

Open AccessReview

The Functions and Phenotypes of Microglia in Alzheimer’s Disease

by Risako Fujikawa and Makoto Tsuda

Cells 2023, 12(8), 1207; https://doi.org/10.3390/cells12081207 - 21 Apr 2023

Cited by 4 | Viewed by 3560

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance [...] Read more.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance of microglia, and resident immune cells in the central nervous system. In addition, new technologies, including single-cell RNA sequencing, have revealed heterogeneous cell states of microglia in AD. In this review, we systematically summarize the microglial response to amyloid-β and tau tangles, and the risk factor genes expressed in microglia. Furthermore, we discuss the characteristics of protective microglia that appear during AD pathology and the relationship between AD and microglia-induced inflammation during chronic pain. Understanding the diverse roles of microglia will help identify new therapeutic strategies for AD. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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46 pages, 11879 KiB

Open AccessReview

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

by Lukas Busch, Simone Eggert, Kristina Endres and Bernd Bufe

Cells 2022, 11(21), 3421; https://doi.org/10.3390/cells11213421 - 29 Oct 2022

Cited by 4 | Viewed by 2801

Abstract

Recent advances have placed the pro-inflammatory activity of amyloid β (Aβ) on microglia cells as the focus of research on Alzheimer’s Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different Aβ variants with variable length and chemical modifications. With [...] Read more.

Recent advances have placed the pro-inflammatory activity of amyloid β (Aβ) on microglia cells as the focus of research on Alzheimer’s Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different Aβ variants with variable length and chemical modifications. With the exception of Aβ_1-42 and Aβ_1-40, the biological significance of most peptides for AD is as yet insufficiently understood. We therefore aim to provide a comprehensive overview of the contributions of these neglected Aβ variants to microglia activation. First, the impact of Aβ receptors, signaling cascades, scavenger mechanisms, and genetic variations on the physiological responses towards various Aβ species is described. Furthermore, we discuss the importance of different types of amyloid precursor protein processing for the generation of these Aβ variants in microglia, astrocytes, oligodendrocytes, and neurons, and highlight how alterations in secondary structures and oligomerization affect Aβ neurotoxicity. In sum, the data indicate that gene polymorphisms in Aβ-driven signaling pathways in combination with the production and activity of different Aβ variants might be crucial factors for the initiation and progression of different forms of AD. A deeper assessment of their interplay with glial cells may pave the way towards novel therapeutic strategies for individualized medicine. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses Ⅱ)

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