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Neuroinflammation Pathway

Neuroinflammatory response is primarily an inherent protective mechanism in the central nervous system (CNS). In intact nerves of the CNS, glial cells (including astrocytes and microglia) play a key role in critical support, and can respond to any degree of CNS injury and disease. They produce various neurotrophic factors and cell-surface mediators with anti-inflammatory activities (e.g. insulinlike growth factors 1 [IGF1], stromal-derived factor- 1 [SDF1], vascular endothecial growth factor [VEGF], monocyte chemoattractant protein 1 [MCP-1], fibroblast growth factor-2 [FGF2], arginase-1 [Arg-1], interleukin [IL]-10, resolvins, and ligands for TAM receptors) and quench damage from free radicals and excitotoxins, as well as promote the repair and regeneration of injured neurons. A successful inflammatory response mechanism eliminates invading pathogens, initiating angiogenesis and normal resolution.

However, inflammation in tissue pathology can lead to the production of neurotoxic factors such as cytokines and interleukins that exacerbate the disease states. Neuroinflammation induces and accelerates pathogenesis of numerous neurodegeneration diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS) and Multiple sclerosis (MS).

Excessive and chronic inflammatory responses can cause deleterious effects involving immune cells, CNS-resident cells and signaling molecules. Both Peripheral-derived and intrinsically generated (from stressed or damaged neurons) inflammatory stimuli can activate glial cells. These factors includes neuromelanin, a-synuclein, corticotropinreleasing hormone (CRH), substance P (SP), matrix metalloproteinase-3 (MMP-3), adenosine triphosphate (ATP), beta amyloid 1–42 (Aβ1–42) peptide and amyloid precursor proteins. Upon the inducer, inflammatory responses can be initiated by several pattern recognition receptors (PRRs) including the Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE). In addition, glial cells can detect ligands for CD14, P2X and P2Y receptors, cytokine receptors and the intracellular NOD-like receptors (NLRs). Ligation of these receptors by binding to specific ligands may further trigger the signaling transduction pathways of diverse transcriptional and post-transcriptional molecules. For instance, TLRs couple to MyD88 and TRIF signal adaptor proteins, leading to the activation of downstream IkB kinases and MAP kinases which in turn control the activities of multiple transcriptional factors, including nuclear factor kappa B (NF-κB), activator protein 1 (AP-1), and interferon regulator factor (IRF) families, leading to the production of several pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, tumor necrosis factor-α (TNF-α) and interferon-γ (IFNγ). They can also produce reactive oxygen species (ROS) though the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, inducible nitric oxide synthase (iNOS) and cyclooxygenase2 (COX2)-Prostaglandin E2 (PGE2) pathway. These factors mediate neuroinflammation induced neurodegeneration mechanisms, including neuronal apoptosis and necrosis, aberrant synaptic pruning, demyelination and axonal degeneration. Particularly, microglia appear to be the major initial sensors of inflammatory signals, and they secrete inflammatory mediators such as IL-1β and TNF-α that can act on astrocytes to induce secondary inflammatory responses. Factors such as MCP-1, IL-6, IL-17, IFN and RANTES (Regulated upon Activation, Normal T cell Expressed and presumably Secreted, also known as CCL5) released from astrocytes may lead to further activation of microglia.

In addition, inflammatory responses are typically localized and involve communication between immune, vascular, and parenchymal cells. The systemic inflammation-derived proinflammatory cytokines/chemokines and other factors (e.g. IL-1β, IL-8, TNF-α, MMP-9 and MCP-1) cause an increased permeability of the blood brain-barrier (BBB) thereby contributing to the recruitment of peripheral immune cells including monocytes, T and B lymphocytes into the brain, causing additional release of proinflammatory and neurotoxic molecules.

References:

1. Glass C K, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell, 2010, 140(6): 918-934.
2. Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nature Reviews Immunology, 2017, 17(1): 49-59.
3. Shabab T, Khanabdali R, Moghadamtousi S Z, et al. Neuroinflammation pathways: a general review. International Journal of Neuroscience, 2017, 127(7): 624-633.
4. Kempuraj D, Thangavel R, Selvakumar G P, et al. Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Frontiers in cellular neuroscience, 2017, 11: 216.

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