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Neuroinflammation: From Molecular Basis to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 26128

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Special Issue Editor

Dr. Isabella Zanella

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Guest Editor

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
Interests: genetics; neurodegenerative disorders; inflammation; iron metabolism disorders; infectious diseases

Special Issue Information

Dear Colleagues,

Inflammatory conditions within the central nervous system (CNS) may damage neurons and are generally recognized in the pathogenesis of neuroimmune disorders like acquired demyelinating syndromes and autoimmune encephalopathies. Mounting evidence indicates that neuroinflammation also plays a crucial role in the pathogenesis of several neurodegenerative disorders, such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) diseases, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) in addition to acute or chronic infections with CNS involvement, such as HIV infection even under efficient combination antiretroviral therapy (cART), or the recent SARS-CoV-2 infection. Neuroinflammation may indeed be triggered by various stimuli, like infections, traumatic injuries, release of toxic metabolites, abnormal accumulation of proteins or autoimmunity, and is mediated by cytokines, chemokines, and reactive oxygen species (ROS) released by both resident and peripheral cells. While in neuroimmune disorders, like multiple sclerosis, neuroinflammation is driven by blood-derived lymphocytes and monocytes infiltrating the CNS through a disrupted blood–brain barrier, resident reactive glial cells, particularly microglia, are mainly involved in neurodegenerative disorders. Microglia are involved in immune surveillance in the CNS and, when activated, may counteract injuries with a brief and controlled inflammatory response, but their dysfunctional activation may lead to uncontrolled inflammation with continuous release of pro-inflammatory mediators and even recruitment of peripheral immune cells. Microglia senescence may also affect progression of neurodegeneration. While reactive microglia may provide both pro- and anti-inflammatory functions, senescent dystrophic microglia are characterized by reduced motility and phagocytosis, increased ROS production, and a pro-inflammatory state, and could have a significant impact on neuron viability. Reactive microglia are frequently found in brain autopsies of patients suffering from numerous neurodegenerative disorders; however, microglia activation seems nonspecific, and for this reason, neuroinflammation has long been regarded as a secondary effect of neuronal dysfunction or death. Nonetheless, genetics strictly links neuroinflammation and neurodegeneration. In recent years, several genetic variants have been associated to or have been defined as risk factors for neurodegenerative disorders. Variants in TREM2 (triggering receptor expressed on myeloid cells 2), a gene expressed only in microglia, have been associated with AD and FTD. APOE (apolipoprotein E) allele Ɛ4 is the main risk factor for AD: like TREM2, APOE is highly expressed in reactive microglia and TREM2 is involved in the APOE signaling pathway. Variants in PGRN (progranulin), TBK1 (TANK-binding kinase 1), and C9orf72 genes, expressed in the microglia and involved in innate immunity and inflammation, are associated with FTD and ALS. Variants in the LRRK2 (leucine-rich repeat kinase 2) gene are found in patients with PD and immunological disorders, in which this gene is highly expressed in activated microglia and peripheral blood cells and is also involved in innate immunity and inflammation. Understanding the molecular mechanisms of neuroinflammation will be crucial to develop new therapeutic approaches of disorders that affect the CNS.

With this Special Issue, we aim to provide a more comprehensive overview of the role of neuroinflammation. Hence, we are inviting researchers to contribute original research articles and reviews exploring the molecular basis of neuroinflammation in CNS disorders of any kind, from classical neuroimmune disorders to neurodegenerative disorders and neuroinflammatory conditions linked to infectious diseases like HIV and SARS-CoV-2 infections. Contributions from all research areas, including disease modeling, human neuropathology, biochemical, molecular, and clinical studies, genomics, proteomics, or therapeutic interventions are welcome.

Dr. Isabella Zanella
Guest Editor

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Keywords

neuroinflammation
CNS disorders
neurodegenerative disorders
Parkinson’s disease (PD)
Alzheimer’s disease (AD)
Huntington’s disease (HD)
frontotemporal dementia (FTD)
amyotrophic lateral sclerosis (ALS)
infections
HIV
SARS-CoV-2
genetics

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 159 KiB

Open AccessEditorial

Neuroinflammation: From Molecular Basis to Therapy

by Isabella Zanella

Int. J. Mol. Sci. 2024, 25(11), 5973; https://doi.org/10.3390/ijms25115973 - 29 May 2024

Viewed by 1268

Abstract

Neuroinflammatory conditions in the central nervous system (CNS) are implicated in the pathogenesis of several neuroimmune disorders such as acquired demyelinating syndromes, autoimmune encephalopathies, acute or chronic bacterial and viral CNS infections as well as multiple sclerosis (MS) [...] Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

Research

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15 pages, 5895 KiB

Open AccessArticle

Torpor-like Hypothermia Induced by A1 Adenosine Receptor Agonist: A Novel Approach to Protect against Neuroinflammation

by Kang Fu, Chunlei Hui, Xinyuan Wang, Tingting Ji, Xiuqing Li, Rui Sun, Chunlei Xing, Xi Fan, Yuanqing Gao and Li Su

Int. J. Mol. Sci. 2023, 24(13), 11036; https://doi.org/10.3390/ijms241311036 - 3 Jul 2023

Viewed by 2129

Abstract

Hypothermia is a promising clinical therapy for acute injuries, including neural damage, but it also faces practical limitations due to the complexities of the equipment and procedures required. This study investigates the use of the A1 adenosine receptor (A1AR) agonist N6-cyclohexyladenosine (CHA) as a more accessible method to induce steady, torpor-like hypothermic states. Additionally, this study investigates the protective potential of CHA against LPS-induced sepsis and neuroinflammation. Our results reveal that CHA can successfully induce a hypothermic state by activating a neuronal circuit similar to the one that induces physiological torpor. This state is characterized by maintaining a steady core body temperature below 28 °C. We further found that this torpor-like state effectively mitigates neuroinflammation and preserves the integrity of the blood–brain barrier during sepsis, thereby limiting the infiltration of inflammatory factors into the central nervous system. Instead of being a direct effect of CHA, this protective effect is attributed to inhibiting pro-inflammatory responses in macrophages and reducing oxidative stress damage in endothelial cells under systemic hypothermia. These results suggest that A1AR agonists such as CHA could potentially be potent neuroprotective agents against neuroinflammation. They also shed light on possible future directions for the application of hypothermia-based therapies in the treatment of sepsis and other neuroinflammatory conditions. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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12 pages, 4635 KiB

Open AccessArticle

Cabotegravir Exposure of Zebrafish (Danio rerio) Embryos Impacts on Neurodevelopment and Behavior

by Daniela Zizioli, Isabella Zanella, Luca Mignani, Melania Degli Antoni, Francesco Castelli and Eugenia Quiros-Roldan

Int. J. Mol. Sci. 2023, 24(3), 1994; https://doi.org/10.3390/ijms24031994 - 19 Jan 2023

Cited by 9 | Viewed by 2596

Abstract

As most new medications, Cabotegravir (CAB) was recently approved as an antiretroviral treatment of HIV infection without in-depth safety information on in utero exposure. Although no developmental toxicity in rats and rabbits was reported, recent studies demonstrated that CAB decreases pluripotency of human embryonic stem cells. CAB exposure effects during development were assessed in zebrafish embryos by the Fish Embryo Toxicity test after exposure at subtherapeutic concentrations up to 25× the human C_max. Larvae behavior was assessed by the light–dark locomotion test. The expression of factors involved in neurogenesis was evaluated by whole-mount in situ hybridization. CAB did not cause gross morphological defects at low doses, although pericardial edema, uninflated swim bladder, decreased heartbeats, growth delay, and decreased hatching rate were observed at the highest concentrations. Decreased locomotion was observed even at the subtherapeutic dose, suggesting alterations of nervous system integrity. This hypothesis was supported by the observation of decreased expression of crucial factors involved in early neuronal differentiation in diencephalic and telencephalic dopaminergic areas, midbrain/hindbrain boundary, and craniofacial ganglia. These findings support CAB effects on neurogenesis in zebrafish embryos and suggest long-term follow-up of exposed infants to provide data on drug safety during pregnancy. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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14 pages, 3454 KiB

Open AccessArticle

Microglial FABP4-UCP2 Axis Modulates Neuroinflammation and Cognitive Decline in Obese Mice

by Simon W. So, Kendra M. Fleming, Cayla M. Duffy, Joshua P. Nixon, David A. Bernlohr and Tammy A. Butterick

Int. J. Mol. Sci. 2022, 23(8), 4354; https://doi.org/10.3390/ijms23084354 - 14 Apr 2022

Cited by 8 | Viewed by 2892

Abstract

The microglial fatty-acid-binding protein 4-uncoupling protein 2 (FABP4-UCP2) axis is a key regulator of neuroinflammation in high-fat-diet (HFD)-fed animals, indicating a role for FABP4 in brain immune response. We hypothesized that the FABP4-UCP2 axis is involved in regulating diet-induced cognitive decline. We tested cognitive function in mice lacking microglial FABP4 (AKO mice). Fifteen-week-old male AKO and wild-type (WT) mice were maintained on 60% HFD or normal chow (NC) for 12 weeks. Body composition was measured using EchoMRI. Locomotor activity, working memory, and spatial memory were assessed using behavioral tests (open field, T-maze, and Barnes maze, respectively). Hippocampal microgliosis was assessed via immunohistochemical staining. An inflammatory cytokine panel was assayed using hippocampal tissue. Real-time RT-PCR was performed to measure microglial UCP2 mRNA expression. Our data support that loss of FABP4 prevents cognitive decline in vivo. HFD-fed WT mice exhibited impaired long- and short-term memory, in contrast with HFD-fed AKO mice. HFD-fed WT mice had an increase in hippocampal inflammatory cytokine expression (IFNγ, IL-1β, IL-5, IL-6, KC/GRO(CXCL1), IL-10, and TNFα) and microgliosis, and decreased microglial UCP2 expression. HFD-fed AKO mice had decreased hippocampal inflammatory cytokine expression and microgliosis and increased microglial UCP2 expression compared to HFD-fed WT mice. Collectively, our work supports the idea that the FABP4-UCP2 axis represents a potential therapeutic target in preventing diet-induced cognitive decline. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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19 pages, 3533 KiB

Open AccessArticle

Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model

by Eun-Sook Jeong, Johny Bajgai, In-Soo You, Md. Habibur Rahman, Ailyn Fadriquela, Subham Sharma, Hwang-Un Kwon, So-Yeon Lee, Cheol-Su Kim and Kyu-Jae Lee

Int. J. Mol. Sci. 2021, 22(24), 13313; https://doi.org/10.3390/ijms222413313 - 10 Dec 2021

Cited by 18 | Viewed by 4648

Abstract

Oxidative stress (OS) is one of the causative factors in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s disease (AD) and cognitive dysfunction. In the present study, we investigated the effects of hydrogen (H₂) gas inhalation in trimethyltin (TMT)-induced neurotoxicity and cognitive dysfunction in the C57BL/6 mice. First, mice were divided into the following groups: mice without TMT injection (NC), TMT-only injection group (TMT only), TMT injection + lithium chloride-treated group as a positive control (PC), and TMT injection + 2% H₂ inhalation-treated group (H₂). The TMT injection groups were administered a single dosage of intraperitoneal TMT injection (2.6 mg/kg body weight) and the H₂ group was treated with 2% H₂ for 30 min once a day for four weeks. Additionally, a behavioral test was performed with Y-maze to test the cognitive abilities of the mice. Furthermore, multiple OS- and AD-related biomarkers such as reactive oxygen species (ROS), nitric oxide (NO), calcium (Ca²⁺), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, inflammatory cytokines, apolipoprotein E (Apo-E), amyloid β (Aβ)-40, phospho-tau (p-tau), Bcl-2, and Bcl-2- associated X (Bax) were investigated in the blood and brain. Our results demonstrated that TMT exposure alters seizure and spatial recognition memory. However, after H₂ treatment, memory deficits were ameliorated. H₂ treatment also decreased AD-related biomarkers, such as Apo-E, Aβ-40, p-tau, and Bax and OS markers such as ROS, NO, Ca²⁺, and MDA in both serum and brain. In contrast, catalase and GPx activities were significantly increased in the TMT-only group and decreased after H₂ gas treatment in serum and brain. In addition, inflammatory cytokines such as granulocyte colony-stimulating factors (G-CSF), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) were found to be significantly decreased after H₂ treatment in both serum and brain lysates. In contrast, Bcl-2 and vascular endothelial growth factor (VEGF) expression levels were found to be enhanced after H₂ treatment. Taken together, our results demonstrated that 2% H₂ gas inhalation in TMT-treated mice exhibits memory enhancing activity and decreases the AD, OS, and inflammatory-related markers. Therefore, H₂ might be a candidate for repairing neurodegenerative diseases with cognitive dysfunction. However, further mechanistic studies are needed to fully clarify the effects of H₂ inhalation on TMT-induced neurotoxicity and cognitive dysfunction. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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24 pages, 5772 KiB

Open AccessArticle

The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo

by Noémie Cresto, Camille Gardier, Marie-Claude Gaillard, Francesco Gubinelli, Pauline Roost, Daniela Molina, Charlène Josephine, Noëlle Dufour, Gwenaëlle Auregan, Martine Guillermier, Suéva Bernier, Caroline Jan, Pauline Gipchtein, Philippe Hantraye, Marie-Christine Chartier-Harlin, Gilles Bonvento, Nadja Van Camp, Jean-Marc Taymans, Karine Cambon, Géraldine Liot, Alexis-Pierre Bemelmans and Emmanuel Brouillet Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(13), 6760; https://doi.org/10.3390/ijms22136760 - 23 Jun 2021

Cited by 9 | Viewed by 3181

Abstract

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2^G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2^G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2^G2019S or its “dead” kinase form, ΔLRRK2^DK, and human α-syn with the A53T mutation (AAV-α-syn^A53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-syn^A53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-syn^A53T with AAV-ΔLRRK2^G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-syn^A53T alone or with AAV-ΔLRRK2^DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2^G2019 alone^, through cell-autonomous mechanisms. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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Review

Jump to: Editorial, Research

15 pages, 874 KiB

Open AccessReview

Diabetic Neuropathy of the Retina and Inflammation: Perspectives

by Guzel Bikbova, Toshiyuki Oshitari and Mukharram Bikbov

Int. J. Mol. Sci. 2023, 24(11), 9166; https://doi.org/10.3390/ijms24119166 - 23 May 2023

Cited by 8 | Viewed by 3522

Abstract

A clear connection exists between diabetes and atherosclerotic cardiovascular disease. Consequently, therapeutic approaches that target both diseases are needed. Clinical trials are currently underway to explore the roles of obesity, adipose tissue, gut microbiota, and pancreatic beta cell function in diabetes. Inflammation plays a key role in diabetes pathophysiology and associated metabolic disorders; thus, interest has increased in targeting inflammation to prevent and control diabetes. Diabetic retinopathy is known as a neurodegenerative and vascular disease that occurs after some years of poorly controlled diabetes. However, increasing evidence points to inflammation as a key figure in diabetes-associated retinal complications. Interconnected molecular pathways, such as oxidative stress, and the formation of advanced glycation end-products, are known to contribute to the inflammatory response. This review describes the possible mechanisms of the metabolic changes in diabetes that involve inflammatory pathways. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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25 pages, 1535 KiB

Open AccessReview

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

by Izchel Figarola-Centurión, Martha Escoto-Delgadillo, Gracia Viviana González-Enríquez, Juan Ernesto Gutiérrez-Sevilla, Eduardo Vázquez-Valls and Blanca Miriam Torres-Mendoza

Int. J. Mol. Sci. 2022, 23(2), 643; https://doi.org/10.3390/ijms23020643 - 7 Jan 2022

Cited by 11 | Viewed by 3986

Abstract

HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV. Full article

(This article belongs to the Special Issue Neuroinflammation: From Molecular Basis to Therapy)

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