Microglial Priming in the Central Nervous System

Microglial cells make up about 10 to 15 percent of all the glial cells in the human body, which can be found in the central nervous system (CNS) and play a fundamental role in the human brain. Microglial cells are responsible for maintaining and regulating changes in the physiological and pathological condition of the CNS by changing their morphology, phenotype and function. In an average physiological state, the microglial cells are continuously in charge of controlling their environment. �

However, when the homeostasis of the brain is interrupted, the microglia change into an amoeba-like shape and become a phagocyte where they can actively reveal a variety of antigens. If the homeostasis interruption in the CNS continues, the microglial cells will then trigger at a much stronger state, which is known as microglial priming. Microglia are the “Bruce Banner” of the CNS. However, once they go into protective “Hulk” mode, primed microglia become much more sensitive to stimulation and they have a much stronger possibility of reacting to stimulation, even reacting towards normal cells. �

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Microglial priming can become a double-edged sword. As a matter of fact, primed microglia are created from different phenotypes of microglia and the phenotypes are context-dependent, which means they are associated to the sequence and duration of their exposure to different varieties of stimulation in a variety of pathologies. In the article below, we will demonstrate the effect of microglial priming on the central nervous system (CNS), especially in neurological diseases. �

Role of Microglial Cells in the CNS

Microglial cells are commonly found in the central nervous system (CNS), where they are considered to be one of the most flexible types of brain cells. Microglial cells are created from precursor cells found within mesoderm bone marrow, or more specifically found in the mesodermal yolk sac, and they are divided in different densities throughout several regions of the brain. As mentioned above, microglia will remain in a dormant state when the homeostasis of the brain remains stable. �

Microglia have a small cell body and morphological branches which extend towards all directions to help maintain and regulate the overall function of the CNS. Changes in their microenvironment can trigger microglia into an “activated� state. Research studies have demonstrated that microglia play a fundamental role in brain development and a variety of functions, including synaptic pruning and clearing out cell debris. Moreover, microglia create an immune surveillance system in the human brain and control fundamental processes associated with a variety of pathologies, including the clearance and uptake of A? and abnormal tau protein as well as the production of neurotrophic factors and neuroinflammatory factors. �

Microglial Priming Overview

Microglial priming activates when continuous interruptions in the brain’s microenvironment trigger a much stronger microglial response compared to an initial interruption which simply triggers microglial activation. Primed microglia in the CNS are also much more sensitive to possibly minor stimulation. This increased response involves microglial proliferation, morphology, physiology, and biochemical markers or phenotype. However, these changes will ultimately promote an increase in cytokines and inflammation mediator production which can have a tremendous impact on synaptic plasticity, neuronic survival, individual cognitive and behavioral function. Below is an overview of the effects of microglial priming in the CNS. �

Mechanisms of Microglial Priming in the CNS

The microenvironment of the central nervous system (CNS), by way of instance, is one of the main factors which can affect the microglial cells. Increased oxidative stress, lipid peroxidation and DNA damage associated with brain aging can all commonly trigger microglial priming. Another common factor for microglial priming includes traumatic brain injury. Research studies have shown that traumatic CNS injury activates microglia as well as the development of primed microglia. �

Many research studies have also shown that both focal and diffuse traumatic brain injury increase inflammation in the brain associated with microglia and astrocytes. CNS infections can also trigger microglial priming where viruses are the main cause of CNS infection. Both DNA and RNA viruses can trigger microglial priming including microglia and astrocytes. Recent research studies have shown that complement dysfunction can change the expression of complement receptors and trigger microglial priming after continuous activation following a variety of functions, including synapse maturation, immune product clearance, hematopoietic stem/progenitor cells (HSPC) mobilization, lipid metabolism, and tissue regeneration. �

Moreover, research studies have shown that there is increased priming of the microglia in a variety of neurological diseases. By way of instance, microglial cells with a morphological phenotype are found in large numbers in the human brain. In the last several years, research studies have suggested that neuroinflammation can continuously activate the microglia and trigger microglial priming. Furthermore, all of the previously mentioned situations are closely associated with neuroinflammation. Research studies have also demonstrated that neuroinflammation, as well as microbial debris and metabolic effects, are associated with central sensitization in neurological diseases, such as fibromyalgia, also referred to as the “brain on fire”. �

In the context of the previous situations mentioned above, microglia are primed though a series of pro-inflammatory stimulation, such as lipopolysaccharide (LPS), pathogenetic proteins (e.g., A?), ?synuclein, human immunodeficiency virus (HIV)-Tat, mutant huntingtin, mutant superoxide dismutase 1 and chromogranin A. There is also a variety of signaling pathways and it is common for different types of cells to express special pattern recognition receptors (PRRs) which can affect inflammatory signaling pathways. By way of instance, several signaling pathways, known as pathogen-associated molecular patterns (PAMPs), which can commonly increase in infected tissue, could also control microbial molecules. �

Additionally, peptides or mislocalized nucleic acids identified as misfolded proteins through a series of pathways, known as danger-associated molecular patterns (DAMPs), can also cause microglial priming. Toll-like receptors (TLRs) and carbohydrate-binding receptors commonly function in these pathways. There are also many different receptors found in microglia, including triggering receptors expressed on myeloid cells (TREM), Fc? receptors (Fc?Rs), CD200 receptor (CD200R), receptor for advanced glycation end products (RAGE), chemokine receptors (CX3CR1, CCR2, CXCR4, CCR5, and CXCR3), which can be recognized and mixed in with other signaling pathways, although some pathways are still not clear. �

Consequences of Microglial Priming in the CNS

Microglia show a low rate of mitosis in their normal state and a high rate of proliferation after microglial priming, showing that the microglia have the ability to affect cell turnover and pro-inflammation stimulation. With continued stimulation, microglia activate from their resting state, changing into amoeboid microglial cells in morphology. However, the changes in the shape of the microglia cannot differentiate the characteristics of microglial activation and the function of primed microglia depends on their phenotypes which are associated with receptors and molecules which they create and recognize. �

The different types of tissue macrophages, under microenvironmental impetus, are able to differentiate M1 and M2 phenotypes. First, M1 polarization, also known as classical activation, ultimately needs interferon-? (IFN-?) to be mixed with TLR4 signaling which then causes the production of inducible nitric oxide synthases (iNOS), reactive oxygen species (ROS), proinflammatory cytokines, and finally, ultimately reduces the release of neurotrophic factors, ultimately causing inflammation with increased markers of main histocompatibility complex II (MHC II), interleukin-1? (IL-1?) and CD68. �

Moreover, M2 polarization, also known as alternative activation, is ultimately believed to be associated with tissue-supportive in the situation of wound healing, reducing inflammation and improving tissue repair of collagen form. They trigger in response to IL-4 and IL-13 in vivo. M2 polarization is characterized by the increased expression of neurotrophic factors, proteases, enzymes arginase 1 (ARG1), IL-10 transforming growth factor-? (TGF-?), scavenger receptor CD206 and coagulation factors as well as improving phagocytic activity. As a matter of fact, there are currently no clear boundaries between the two polarizations and the M1 phenotype shares many similar characteristics with the M2 phenotype. �

Another phenotype of primed microglia, known as acquired deactivation, has been recently discovered. This new phenotype overlaps with M2 and has the ability to improve anti-inflammatory and functional recovery. Additionally, a research study conducted ultra-structural analyses and identified a brand-new phenotype, known as �dark microglia�, which is rarely seen in the microglial cell’s resting state. Systemic inflammation triggers microglia into an activated state to promote cell and tissue recovery and achieve homeostasis. Microglial priming is ultimately the second interruption in the CNS microenvironment. �

The primed microglia is a double-edged sword for brain health. Many research studies in vivo and in vitro have shown that neurological diseases are associated with microglial activation. The inflammatory phenotypes of the microglia create neurotoxic factors, mediators and ROS which can affect the CNS. Primed microglia play a fundamental and beneficial role in neuronal regeneration, repair, and neurogenesis. Primed microglia are also much more sensitive and respond much stronger to brain injury, inflammation, and aging as well as increase the activation of microglial cells by switching from an anti-inflammation, potentially protective phenotype to a pro-inflammation destructive phenotype, as shown in (Figure 1). �

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In the early stages of microglial priming, the ability and function to phagocytize cell debris, misfolded proteins, and inflammatory medium are increased where more protective molecules, such as IL-4, IL-13, IL-1RA, and scavenging receptors, are created. The changes can affect wound healing and damage tissue repairment, neuron protection, and homeostasis recovery. Classically activated microglia (M1) make up a large proportion of all microglia and promote an increased creation of neurotoxic factors, such as IL-1?, TNF-?, NO and H2O2 (6), where more microglia are primed immediately afterward. �

This increased and extended neuroinflammation caused by primed microglia can ultimately be associated with the development and clustering of the protein tau and A?. Furthermore, it can lead to loss of neurons as well as the decrease of cognitive function and memory, such as in Alzheimer’s disease. Although the mechanisms are not clear enough, people have reached an agreement that primed microglia cause a chronic proinflammatory response and a self-perpetuating cycle of neurotoxicity. And this is believed to be the key factor in brain health issues resulting in neurological diseases. �

Microglia are known as the protectors of the brain and they play a fundamental role in maintaining as well as regulating the homeostasis of the CNS microenvironment. Constant stimulation causes the microglia to trigger at a much stronger state, which is known as microglial priming. Microglial cells are the “Bruce Banner” of the CNS. However, once they go into protective “Hulk” mode, primed microglia become much more sensitive to stimulation and they have a much stronger possibility of reacting to stimulation, even reacting towards normal cells. �- Dr. Alex Jimenez D.C., C.C.S.T. Insight

Microglial cells make up about 10 to 15 percent of all the glial cells in the human body, which can be found in the central nervous system (CNS) and play a fundamental role in the human brain. Microglial cells are responsible for maintaining and regulating changes in the physiological and pathological condition of the CNS. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �

Curated by Dr. Alex Jimenez �

Additional Topic Discussion: Chronic Pain

Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.

Neural Zoomer Plus for Neurological Disease

Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural Zoomer^TM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural Zoomer^TM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural Zoomer^TM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �

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