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Type: Original article
Title: Microglia: the enigmatic immune cell of the central nervous system
Authors: Benusa SD1,2 and Dupree JL1,2
Affiliations: 1Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond VA 23298
2Research Division, HH McGuire VA Medical Center, Richmond, VA 23249
Abstract: Microglia were first characterized by Rio Hortega over 100 years ago with our understanding of the function of these cells blossoming over the past 20 years. We now recognize that microglia are involved in a plethora of activities during CNS development including synaptic refinement, apoptotic cell clearing and neuronal survival. These cells also have defined roles in the adult brain which include mediating synaptic plasticity and immune surveillance. Consequential to surveillance, microglia detect threats to the CNS driving dramatic changes in cell morphology and factor expression. Morphologic changes include shortening of processes with reduced process branching and enlargement of the microglial cell body. Changes in factor expression are far less conserved and more complex. In an effort to simplify the discussion and study of these cells, nomenclature originally ascribed to define states of macrophage activation, known as M1 (classic) and M2 (alternative), has been assigned to microglia. However, such classification for microglia is an oversimplification, at best, and, more likely, an inaccurate representation of the complex pathologic phenotypes presented by these cells. Here, we review the use of the M1/M2 terminology and we present novel microarray data from 3 distinct inflammatory models commonly used to study microglial response. Our findings in conjunction with recent reports from other labs, further support the inadequacy of the M1/M2 categorizations and the need for a more comprehensive nomenclature that accurately portrays the functional complexity of these enigmatic cells.
Title: Mitochondrial bioenergetics and the pro-inflammatory response of microglia
Authors: G. Jean Harry and Gabrielle M. Childers
Affiliations: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA
Abstract: Increasing evidence has placed the mitochondria as a pivotal signaling platform in macrophages. Stimulation of macrophages into a classic pro-inflammatory state is known to decrease oxidative phosphorylation and increase glycolysis. This glycolytic shift is driven by nitric oxide production, which directly inhibits electron transport. This then allows the repurposing of the mitochondria for the production of mtROS by complex I, a crucial signaling molecule for immune cell activation. The availability of Kreb’s cycle intermediates and quicker ATP output with glycolysis also allows for the quick generation and release of cytokines and other signaling molecules. (Mills et al. 2017) Glycolysis and complex I have both been found necessary for initiation of the IL-1B cytokine response in macrophages. While taking on macrophage-like properties, microglia are unique in their source of origin, microenvironment, and longevity. Microglia have been found to, like macrophages, shift their energy dynamics to a primarily glycolytic pro-inflammatory response and also to a primarily oxidative phosphorylation anti-inflammatory response. (Orhelia et al., 2015). While it is assumed that this shift in mitochondrial function would underlie the pro-inflammatory response, the necessity of the mitochondria has yet to be determined. The manuscript shall review the current state of the science with regards to our understanding of mitochondrial functioning in the activation of microglia and provide original data examining the effects of limiting glycolytic function and mtDNA production on the ability of microglia to mount a pro-inflammation response to LPS stimulation.
Title: Microglial process convergence on axonal segments in health and disease
Authors: Savannah Benusa and Audrey Lafrenaye
Affiliations: Department of Anatomy and Neurobiology, Virginia Commonwealth University
Abstract: Microglia dynamically interact with neurons influencing the development, structure, and function of neuronal networks. Recent studies suggest microglia may also influence neuronal activity by interacting with axonal domains responsible for action potential initiation and propagation. However, the nature of these non-phagocytic microglial process interactions is not understood. Microglial-axonal contact is present early in development and persists through adulthood implicating a role for these cells in the regulation of axonal integrity in both the developing and mature CNS. Moreover, increases in microglial-axonal contact have been described in disease states such as multiple sclerosis (MS) and traumatic brain injury (TBI). Depending on the disease state there is increased association with specific axonal segments. In MS, there is enhanced contact with the AIS, while in TBI, microglia alter interactions specifically with proximal axonal swellings of injured axons. In this article, we review the role of non-phagocytic physical interactions of microglial processes with axonal segments, analyzing their associations with various axonal domains and how these interactions may differ within the time course of disease. Furthermore, we discuss potential functional consequences of these interactions and therapeutic approaches that may enhance neuroprotection.
Type: Original Article
Title: Telmisartan reduces LPS-mediated inflammation and induces autophagy and death of microglia.
Authors: Kwame O Affram, Zachary C Janatpour, Nagesh Shanbhag, Sonia Villapol and Aviva J. Symes
Affiliations: Uniformed Services University, Bethesda, MD
Abstract: Chronic neuroinflammation mediated by persistent microglial activation is strongly associated with neurodegeneration. Reducing microglial activation as well as the population of activated microglia could therefore be of benefit in neurodegenerative disorders. Angiotensin receptor blockers (ARBs) have prominent anti-inflammatory activity in some cell types, and have been proposed as potential treatments for neurodegenerative diseases and neurotrauma. Although all ARBs act as antagonists at the angiotensin II receptor I, some ARBs also activate or inhibit other signaling pathways allowing for a multi modal mechanism of action. The mechanism of anti-inflammatory action of the ARBs is incompletely understood although recently the ARB telmisartan was shown to reduce microglial activation via AMPK signaling. In this study we compared the ARBs for their ability to reduce LPS stimulation of primary microglia or BV2 cells. We find that telmisartan showed the greatest efficacy to reduce LPS stimulated reactive oxygen species and nitric oxide production in primary microglia and BV2 microglial cells. Telmisartan, but not the other ARBs dose dependently induced AMPK phosphorylation in BV2 cells and reduced phosphorylation of the downstream kinase mTOR. Telmisartan’s reduction of LPS stimulated reactive oxygen species was partially dependent on AMPK activity as the AMPK inhibitor compound C partially attenuated this effect. Telmisartan also uniquely induced markers of autophagy in microglia and reduced microglial viability. Telmisartan’s toxicity to microglia was partially ameliorated by an inhibitor of autophagy and a pan-caspase inhibitor. We conclude that telmisartan is able to activate AMPK and reduce mTOR activation and hence induce autophagy in microglia . Telmisartan treatment leads to a reduction of microglial viability, through autophagy or through apoptosis. Telmisartan’s toxicity to microglia also serves as an alternative anti-inflammatory mechanism to reduce the activated microglial population.
Title: Differential roles of resident microglia and blood-borne macrophages in neuroinflammation in pathophysiology
Authors: Junya Tanaka
Affiliations: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan
Abstract: Resident microglia rapidly become activated in response to even minor pathologic changes in the central nervous system, while releasing various cytokines, growth factors, reactive oxygen species and others as well as eliminating synapses and degenerating cells through phagocytosis. Furthermore, monocytes in circulation invade into the inflamed brain tissues and turns into brain macrophages that also produce a number of bioactive substances and engage in phagocytosis. In this article, the pathophysiological roles of resident microglia and blood-borne macrophages in animal models of Parkinson’s disease, stroke and traumatic brain injury are discussed. Both cell types exert both ameliorating and aggravating effects on the pathologic brains, and their differential roles are addressed in this review. Furthermore, this article compares the effects of various pharmacological interventions to induce the phenotypic changes of both cell types for the better outcome of the pathologic brains.
Title: the sex differences in microglia responses to inflammatory insults
Authors: Natalia Yanguas-Casás
Affiliations: Departamento de Neurobiología Funcional y de Sistemas, Grupo de Neuroinmunología, Instituto Cajal, CSIC, Spain
Abstract: Microglia are the resident immune cells in the brain and are essential in the maintenance of homeostasis in this tissue. These cells are key producers of immune molecules, such as cytokines and chemokines, critical for normal brain development, affecting neurogenesis, axonal migration, synapse formation and function, and programmed cell death, among others. Sex differences exist in many of these processes throughout brain development up to adulthood and the aged brain. In the last few years, sex differences in microglia responses, brain colonization, number and morphology within the developing brain have drawn the attention of researchers as a potential explanation to the sex differences in the brain and their relevance in the incidence, prevalence and outcome of many neurological disorders. In this review, we take an insight in the sex differences of microglial cell functions and their potential role in physiological as well as in pathological conditions in the brain.
Title: Microglia at the crossroads of pathogen-induced neuroinflammation: friend or foe of the neurovascular unit?
Authors: Ana M. Rodríguez and Guillermo H. Giambartolomei
Affiliations: Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
Abstract: Microglial cells are the resident tissue macrophages of the CNS. Recent findings point that in the steady state the major role of microglia are instructing and regulating the proper function of the neuronal networks and different components of the neurovascular unit in the adult CNS, while providing immune surveillance. Paradoxically, upon infection immune activation of microglia will create an inflammatory environment that will contribute to the clearance of the pathogen, but can in the process, harm nearby components of the neurovascular unit. Most of the knowledge we have of the harmful effect of activated microglia on CNS have risen from studies on neurodegenerative diseases. We will focus on this review on the beneficial and detrimental functions of microglial cells upon infection of the CNS