An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

Abstract

Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system ("neuroinflammation"), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell-cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation.

Keywords: astrocytes; crosstalk; inflammation; mast cells; microglia; neuro-immune; oligodendrocytes; palmitoylethanolamide.

Figure 1

Microglia, like Janus, the two-faced Roman god of beginnings and transitions, display two sides—physiological as well as pathological. While microglial cell activation participates in surveillance that functions to maintain homeostasis and promote synaptic maturation, prolonged exposure to pathogen activators or in settings of systemic inflammation, as may occur in conditions such as diabetes or obesity, can culminate in a state of chronic, non-resolving neuroinflammation. Ultimately, these responses will provoke functional and structural changes and neuronal cell death (neurodegeneration).

Figure 2

Reciprocal interactions between microglia and astrocytes provoke beneficial and harmful effects in the brain. (Left) Physiological actions include microglia phagocytosis/debris clearance, release of anti-inflammatory cytokines/chemokines (), and trophic agents to favor neuronal cell survival. (Right) Non-resolving neuroinflammation results in a pathological, pro-inflammatory activation profile of microglia/mediator production (), blood-brain barrier (BBB) compromise, immune cell infiltration, gliosis, and neuronal cell death [Adapted and extensively modified from Le Thuc et al. (2015). The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects (Figure 3). Copyright © 2015 John Wiley and Sons. With permission].

Figure 3

Mast cell—microglia crosstalk in the release of brain-derived neurotrophic factor (BDNF). ATP-induced BDNF expression and release is mediated by the P2X₄ receptor through a mechanism involving Ca²⁺ entry, induction of Ca²⁺/inositol 1,4,5-trisphosphate/PKC signaling, phosphorylation of IKKα and IKKβ and activation and nuclear translocation of nuclear factor-κB (NF-κB) and gene induction The purinergic P2X₄ receptor acts to release BDNF via mast cell tryptase cleavage/activation of protease-activated receptor 2 (PAR2) on microglia which couples to G proteins and induces canonical phospholipase C (PLC)/Ca²⁺/protein kinase C (PKC) signaling, activation and nuclear translocation of NF-κB, culminating in BDNF gene induction and translation. The latter cells release tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) which can further drive mast cell activation and degranulation and numbers, leading to a potential feedback loop between mast cells and microglia.

Figure 4

Palmitoylethanolamide synthesis and metabolism. N-palmitoyl-phosphatidyl-ethanolamine (N-APE) is converted into palmitoylethanolamide and phosphatidic acid by a plasma membrane-associated N-acylated phosphatidylethanolamine-phospholipase D (PLD). Palmitoylethanolamide (PEA) is broken down to palmitic acid and ethanolamine by fatty acid amide hydrolase (FAAH, which also catabolizes other fatty acid amides) as well as the more selective N-acyl ethanolamine-hydrolyzing acid amidase (NAAA). Tissue levels of palmitoylethanolamide rise under conditions of stress, e.g., peripheral tissue inflammation, neuroinflammation, and pain [Reproduced from Skaper et al. (2014) Mast cells, glia and neuroinflammation: partners in crime? (Figure 2). Copyright © 2013 John Wiley & Sons Ltd. With permission].