Antonio Jose Herrera

Interest in microglial cells as agents involved in neuroinflammation is recent but growing rapidly, although we still do not know if their overall action is protective or damaging to neurons; the search 'Neuroinflammation + Microglia + Protective' yields approximately the same result as 'Neuroinflammation + Microglia + Damaging'.Microglia act as homeostatic cells in the central nervous system. In recent years, research on microglia has focused on defining their role in brain physiology, both in health and disease. What has been found exceeds previous expectations, as microglial cells actively participate not only in surveillance tasks of nervous tissue but also in different aspects of neurogenesis, neuronal connectivity, synaptic control (through pruning, for example), and myelination, among others.When nervous tissue is threatened or damaged, microglia initiate a beneficial acute inflammatory process characterized by the release of inflammatory mediators and phagocytosis of cellular debris. This process ends after eliminating the threat (pathogens, for example) and repairing the damage. However, the alteration of this physiological self-limited acute healing inflammatory process, for reasons not yet well understood, leads to a self-sustained neuroinflammatory state. In this state, inflammation produces damage, and damage, in turn, produces more inflammation in a continuous cycle.The topic "15 Years of Frontiers in Cellular Neuroscience: The Dual Role of Microglia in (Neuro)inflammation" explores some of the microglia-mediated processes that influence brain and neuronal homeostasis, as well as the factors that modify them, such as stress.Traumatic brain injury (TBI) affects tens of millions of people worldwide, creating an unbearable burden for public health systems and for affected individuals and families. This is due to the high number of hospitalizations and deaths it causes, as well as the long-lasting functional deficits (cognitive, psychiatric, and physical) experienced. Boland and Kokiko-Cochran (2024; https://doi.org/10.3389/fncel.2024.1352790) review the role of microglia in TBI, their relationship with other cell types (neurons, astrocytes, and peripheral immune cells), and methods to manipulate them, focusing on the use of colony-stimulating factor 1 receptor (CSF1R) inhibitors and the results obtained in studies using these inhibitors in TBI.As TBI alters baseline levels of stress hormones, as well as the response to external stressors (including medical-related psychological stress), different natural and synthetic glucocorticoids (GC) have been used to treat some of the chronic side effects associated with persistent neuroinflammation.Taylor and Kokiko-Cochran (2024; https://doi.org/10.3389/fncel.2024.1351685) review the stress response and glucocorticoid signaling in the context of TBI. They suggest that the therapeutic approach based on GC and manipulation of their receptors (GR) should be modified to be specific for each cell type, focusing on their effects on microglia and the associated neuroinflammation.Neurodegenerative diseases affect a growing number of individuals worldwide. Alzheimer's disease alone, the most prevalent among them, is estimated to affect more than 100 million people by 2050. While TBI is an enormous public health problem, it is difficult to express in words the devastating impact that neurodegenerative diseases have today and will have in our near future. It is a fact that microglial functions are dysregulated in these diseases, which explain why many of the scientific articles counted in the figure try to understand how this alteration occurs and find ways to prevent or even reverse it.Pro-inflammatory microglia require high amounts of glucose to function. Chung et al. (2024; https://doi.org/10.3389/fncel.2024.1374298) study the role of a homeostatic protein, the Regulator of G-protein Signaling 10 (RGS10), in maintaining microglial homeostasis under conditions of hyperglycemia and neuroinflammation related to the disease. Their results support that RGS10, abundant in microglia and downregulated in neurodegenerative diseases, is a negative regulator of microglial activation, which develops with the production of proinflammatory cytokines and reactive oxygen species.To date, treatments available for Alzheimer's disease are purely palliative (fundamentally inhibiting acetylcholinesterase and trying to keep excitotoxicity under control), although recent advances have been made using immunotherapy. Roshan et al. (2024; https://doi.org/10.3389/fncel.2024.1440559) propose a new therapeutic approach by adapting methods used in the treatment of various forms of cancer to Alzheimer's disease: Radiation therapy, specifically through the adaptation of boron neutron capture therapy (BNCT). Their results show a strong pro-inflammatory induction of microglia, with induced phagocytosis that helps eliminate beta-amyloid. Of great interest is that this therapy seems to induce microglia transiently, without long-term alterations, avoiding the self-sustained neuroinflammatory state in which inflammation produces damage and damage produces inflammation endlessly.

Editorial: Factors contributing to dopaminergic cell death

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state’s proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation). Molecular signatures of DAM and proinflammatory microglia (highly pro-oxidant) have shown clear differences, yet a partial overlapping gene profile is evident between both phenotypes. The switch activation of homeostatic microglia into reactive microglia relies on the selective activation of key surface receptors involved in the maintenance of brain homeostasis (a.k.a. pattern recognition receptors, PRRs). Two relevant PRRs are toll-like receptors (TLRs) and triggering receptors expressed on myeloid cells-2 (TREM2), whose selective activation is believed to generate either a proinflammatory or a DAM phenotype, respectively. However, the recent identification of endogenous disease-related ligands, which bind to and activate both TLRs and TREM2, anticipates the existence of rather complex microglia responses. Examples of potential endogenous dual ligands include amyloid β, galectin-3, and apolipoprotein E. These pleiotropic ligands induce a microglia polarization that is more complicated than initially expected, suggesting the possibility that different microglia subtypes may coexist. This review highlights the main microglia polarization states under disease conditions and their leading role orchestrating oxidative stress.

Caspase-8 inhibition represses initial human monocyte activation in septic shock model

This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson’s disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of PD.

Neurodegenerative diseases are characterized by a progressive deterioration of brain function, with a consequent significant decline in the quality of life of patients and their families. Due to the concurrent increase in life expectancy, the incidence of these diseases has been increasing over the last years and thus there is a growing interest in finding potential risk factors. This review focuses on the correlation between peripheral inflammatory diseases and neurodegeneration, in particular on the relationship between gastrointestinal disorders and Parkinson's disease, especially through the so called gut-brain axis.

Alzheimer’s disease is the most common cause of dementia in the elderly. Although the primary cause of the disease is presently unknown, to date several risk factors have been described. Evidence suggests that one of these risk factors could be chronic stress. The aim of this work is to demonstrate that chronic stress is able to induce Alzheimer’s disease features after the administration of nontoxic doses of sodium azide. We found that chronic stress increases the levels of several proteins involved in Alzheimer’s disease pathogenesis, such as presenilin 1, presenilin 2, and S100β, besides inducing the aggregation of Tau, ubiquitin, and β-amyloid proteins in the hippocampus. More important, our work shows a synergistic effect of stress and sodium azide treatment leading to significant neuronal death in the mouse hippocampus. Our results point out that chronic stress is a risk factor contributing to amplify and accelerate Alzheimer’s disease features in the hippocampus.