Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases

Lima, Maria Érica de Oliveira; Barbosa-Silva, Maria Carolina; Maron‐Gutierrez, Tatiana

doi:10.3389/fncel.2022.878987

Cited by 18 publications

(7 citation statements)

References 185 publications

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“…Exaggerated inflammatory responses by activated microglia, as demonstrated here, may impair homeostatic functions and lead to neuronal damage, including impairment of synaptic connectivity ( Lima et al, 2022 ). Therefore, neuronal damage triggered by H7N7 IAV could be mediated by microglia that engulf and digest synaptic terminals by phagocytosis with the help of lysosomes.…”

Section: Resultsmentioning

confidence: 92%

Influenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection

et al. 2023

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Influenza A virus (IAV) subtypes are a major cause of illness and mortality worldwide and pose a threat to human health. Although IAV infection is considered a self-limiting respiratory syndrome, an expanded spectrum of cerebral manifestations has been reported following IAV infection. Neurotropic IAVs, such as the H7N7 subtype, are capable of invading the central nervous system (CNS) and replicating in brain cells, resulting in microglia-induced neuroinflammation. Microglial cells, the brain’s resident immune cells, are instrumental in the inflammatory response to viral infection. While activation of microglia is important to initially contain the virus, excessive activation of these cells leads to neuronal damage. Previous studies have shown that acute and even long-term IAV-induced neuroinflammation leads to CNS damage. Therefore, the search for possible preventive or therapeutic strategies is of great importance. In this study, we investigated the potential effect of vaccination against acute neuroinflammation induced by H7N7 infection and subsequent neuronal damage in the hippocampus, a particularly vulnerable brain region, comparing young and aged mice. Immunosenescence is one of the striking pathophysiological changes during mammalian aging that leads to “inflammaging” and critically limits the protection by vaccines in the elderly. The results suggest that formalin-inactivated H7N7 vaccine has a preventive effect against the inflammatory responses in the periphery and also in the CNS after H7N7 infection. Cytokine and chemokine levels, increased microglial density, and cell volume after H7N7 infection were all attenuated by vaccination. Further structural analysis of microglial cells also revealed a change in branching complexity after H7N7 infection, most likely reflecting the neuroprotective effect of the vaccination. In addition, synapse loss was prevented in vaccinated mice. Remarkably, engulfment of post-synaptic compartments by microglia can be proposed as the underlying mechanism for spine loss triggered by H7N7 infection, which was partially modulated by vaccination. Although young mice showed better protection against neuroinflammation and the resulting deleterious neuronal effects upon vaccination, a beneficial role of the vaccine was also observed in the brains of older mice. Therefore, vaccination can be proposed as an important strategy to prevent neurological sequelae of H7N7 infection.

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Section: Resultsmentioning

confidence: 92%

Influenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection

et al. 2023

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“…PolyI:C exposure early in life induces microglial priming, a state in which the cells respond more to stimuli. In summary, early life exposure to PolyI:C may lead to changes in microglial state and function, priming these cells for subsequent immune challenges, not bene cial to brain function 45 , i.e., leading to behavioral alterations such as cognitive de cits.…”

Section: Discussionmentioning

confidence: 99%

Long-term environmental enrichment prevents schizophrenia-like abnormalities and promotes hippocampal Slc6a4 gene demethylation in mice submitted to a two-hit model

Arraes

Barreto

Vasconcelos

et al. 2023

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In the last decades, attention has been called to the need for preventive strategies against neurodevelopmental disorders. In the present study, we aimed to investigate the impacts of long-term environmental enrichment (EE) in preventing behavioral, neurochemical, and epigenetic changes in mice exposed to the two-hit model of schizophrenia. To this end, we used neonatal Swiss mice exposed to the viral mimetic polyinosinic:polycytidylic acid (PolyI:C) as first-hit on postnatal days (PND) 5–7 or sterile saline (zero-hit). On PND21, mice were randomly allocated to cages with standard (SE) or enriched environment (EE). From PND35-44, PolyI:C group was exposed to unpredictable stressors as second-hit. On PND70, after EE's last exposure, the animals underwent behavioral testing, and the hippocampus was collected for biochemical (Iba-1 and DCX) and epigenetic (SLC6A4 gene) analysis. The results showed that fifty days of EE exposure to two-hit mice, i.e., from infancy to adulthood, prevented sensorimotor gating deficits and working memory impairment while improving locomotor and exploratory activity. Furthermore, EE prevented hippocampal Iba-1 increased expression. EE-exposed mice presented increased hippocampal DCX expression. In addition, hippocampal demethylation of the SLC6A4 gene (serotonin transporter), an epigenetic reprogramming mechanism, was observed in the two-hit group submitted to EE. Our results reveal the preventive effects of long-term EE in mice exposed to the two-hit model of schizophrenia by mechanisms related to increased neurogenesis, reduced microglia reactivity, and epigenetic regulation of serotonergic signaling.

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“…Macrophages and microglia can develop a primed proinflammatory profile consisting of an amplified response mRNA expression, protein translation, and morphological changing when exposed to stress (Niraula et al 2017 ), aging (Norden and Godbout 2013 ; Niraula et al 2017 ), chronic systemic inflammation (Chouhan et al 2022 ), and obesity (Alexaki 2021 ). Due to this maladaptive response, microglia exacerbate their inflammatory response when an acute event happens, such as traumatic brain injury (TBI) (Lifshitz et al 2007 ), pathogen-associated neuroinflammation (Furr and Marriott 2012 ; Lima et al 2022 ), and stroke (Qin et al 2019 ), among others. As a result of this stage, microglia show a high rate of proliferation after being primed and present impairments in regulatory systems, circumstances that make microglia resistant to negative feedback and functionally compromised, enhancing resultant damage, and worsening the patient’s prognosis (Norden et al 2015 ).…”

Section: Generalities Of Microglial Cellsmentioning

confidence: 99%

Possible Implications of Obesity-Primed Microglia that Could Contribute to Stroke-Associated Damage

et al. 2023

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Microglia, the resident macrophages of the central nervous system, are essential players during physiological and pathological processes. Although they participate in synaptic pruning and maintenance of neuronal circuits, microglia are mainly studied by their activity modulating inflammatory environment and adapting their phenotype and mechanisms to insults detected in the brain parenchyma. Changes in microglial phenotypes are reflected in their morphology, membrane markers, and secreted substances, stimulating neighbor glia and leading their responses to control stimuli. Understanding how microglia react in various microenvironments, such as chronic inflammation, made it possible to establish therapeutic windows and identify synergic interactions with acute damage events like stroke. Obesity is a low-grade chronic inflammatory state that gradually affects the central nervous system, promoting neuroinflammation development. Obese patients have the worst prognosis when they suffer a cerebral infarction due to basal neuroinflammation, then obesity-induced neuroinflammation could promote the priming of microglial cells and favor its neurotoxic response, potentially worsening patients’ prognosis. This review discusses the main microglia findings in the obesity context during the course and resolution of cerebral infarction, involving the temporality of the phenotype changes and balance of pro- and anti-inflammatory responses, which is lost in the swollen brain of an obese subject. Graphical Abstract Obesity enhances proinflammatory responses during a stroke. Obesity-induced systemic inflammation promotes microglial M1 polarization and priming, which enhances stroke-associated damage, increasing M1 and decreasing M2 responses.

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Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases

Cited by 18 publications

References 185 publications

Influenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection

Influenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection

Long-term environmental enrichment prevents schizophrenia-like abnormalities and promotes hippocampal Slc6a4 gene demethylation in mice submitted to a two-hit model

Possible Implications of Obesity-Primed Microglia that Could Contribute to Stroke-Associated Damage

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