Immunology primer for neurosurgeons and neurologists part 2: Innate brain immunity

Abstract

Over the past several decades we have learned a great deal about microglia and innate brain immunity. While microglia are the principle innate immune cells, other cell types also play a role, including invading macrophages, astrocytes, neurons, and endothelial cells. The fastest reacting cell is the microglia and despite its name, resting microglia (also called ramified microglia) are in fact quite active. Motion photomicrographs demonstrate a constant movement of ramified microglial foot processes, which appear to be testing the microenvironment for dangerous alteration in extracellular fluid content. These foot processes, in particular, interact with synapses and play a role in synaptic function. In event of excitatory overactivity, these foot processes can strip selected synapses, thus reducing activation states as a neuroprotective mechanism. They can also clear extracellular glutamate so as to reduce the risk of excitotoxicity. Microglia also appear to have a number of activation phenotypes, such as: (1) phagocytic, (2) neuroprotective and growth promoting, or (3) primarily neurodestructive. These innate immune cells can migrate a great distance under pathological conditions and appear to have anatomic specificity, meaning they can accumulate in specifically selected areas of the brain. There is some evidence that there are several types of microglia. Macrophage infiltration into the embryonic brain is the source of resident microglia and in adulthood macrophages can infiltrate the brain and are for the most part pathologically indistinguishable from resident microglia, but may react differently. Activation itself does not imply a destructive phenotype and can be mostly neuroprotective via phagocytosis of debris, neuron parts and dying cells and by the release of neurotrophins such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). Evidence is accumulating that microglia undergo dynamic fluctuations in phenotype as the neuropathology evolves. For example, in the early stages of neurotrauma and stroke, microglia play a mostly neuroprotective role and only later switch to a neurodestructive mode. A great number of biological systems alter microglia function, including neurohormones, cannabinoids, other neurotransmitters, adenosine triphosphate (ATP), adenosine, and corticosteroids. One can appreciate that with aging many of these systems are altered by the aging process itself or by disease thus changing the sensitivity of the innate immune system.

Keywords: Immune surface receptors; immunoexcitotoxicity; innate immunity; microglia; microglial priming.

Figure 1

Illustration of the stages of microglial activation from a resting (ramified) state, to a primed state and finally to a fully activated phenotype. The exact phenotype and physiology of each stage of activation is determined by a number of extraneuronal molecules and environmental conditions

Figure 2

Illustration of fully activated microglia in a neurodestructive phenotype, with the release of proinflammatory cytokines, chemokines and excitatory amino acids, all acting in concert to damage the surrounding neurons

Figure 3

Illustration of a microglia in a primary reparative phenotype, which can be in either the resting mode or an activated-reparative mode, both of which release neurotrophic factors and antiinflammatory cytokines. This repairs the damage done during neurodestructive microglial activation

Figure 4

Illustration of general cellular anatomy of a TLR type Pattern Recognition Receptor (PRR). The external receptor interacts with specific Pathogen Associated Molecular Patterns (PAMPs) that translates signals to the intracellular signaling pathways for gene activation of defense mechanisms

Figure 5

Illustration of various microorganism-related molecular ligands that can interact with specific TLRs leading to intracellular activation of defensive cell signaling mechanisms

Figure 6

Illustration of lipopolysaccharide (LPS) Gram-negative cell wall molecular component interacting with TLR on microglial membrane surface, which along with co-stimulatory molecule CD14, activates defensive cell signaling. The IL-1 type pro-inflammatory cytokine receptor TIR, plays a major role in microglial activation

Figure 7

Illustration of intracellular TLRs found on the membrane of endosomes, which play a major role in neutralizing viruses I within the cell itself

Figure 8

Schematic demonstrating the link between TNF -α and an enhancement of excitotoxicity via its interaction with glutamate transport proteins, upregulation of glutaminase, suppression of glutamine synthetase, increased trafficking of AMPA calcium-permeable receptors to the synaptic membrane and endocytosis of GABA receptors

Figure 9

Illustration demonstrating the trafficking of AMPA calcium-permeable receptors from the endoplasmic reticulum to the synaptic lipid raft, thus increasing glutamate sensitivity and increasing the internal flow of calcium. We see a condition of crosstalk between TNFR1 receptors and AMPA receptor trafficking mechanisms

Figure 10

Illustration of the combined release of pro-inflammatory cytokines and chemokines along with excitatory amino acids during neurodestructive microglial activation. This demonstrates the interaction between immune factors, reactive oxygen and nitrogen species, lipid peroxidation species and excitotoxicity

Figure 11

Illustration demonstrating chronic neurodegeneration resulting from a failure of activated microglia to switch to a resting state. Under such conditions immunoexcitotoxic cascades persist.