Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

Abstract

Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson’s disease (PD), Alzheimer’s disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1–42 (Aβ1–42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can also enter into the peripheral system through defective BBB, recruit immune cells into the brain, and exacerbate neuroinflammation. We suggest that mast cell-associated inflammatory mediators from systemic inflammation and brain could augment neuroinflammation and neurodegeneration in the brain. This review article addresses the role of some atypical inflammatory mediators that are associated with mast cell inflammation and their activation of glial cells to induce neurodegeneration.

[18F] AV-1451 uptake in corticobasal syndrome: the influence of beta-amyloid and clinical presentation

“…Given the uncertainty however over whether AV-1451 is binding 4R tau, it is also possible that the findings reflect a greater degree of neurodegeneration, i.e. neuronal cell loss, gliosis, or neuroinflammation, in premotor and precentral cortices in patients with AOS as these neurodegenerative processes are observed in corticobasal degeneration [21, 25]. It is less likely that there is more paired helical filament or mixed 3+4R Alzheimer’s type tau in these regions in CBS cases with AOS, as a pathological case study of CBS with AOS showed only 4R tau in these areas [20].…”

Anti‐neuroinflammatory activities of extract and polymethoxyflavonoids from immature fruit peels of Citrus ‘Hebesu’

“…Even though acute neuroinflammation is a protective response, the unstopped inflammatory process leads to chronic inflammation, which is harmful for the healthy state of the brain and its functions (Kempuraj et al, ). Chronic neuroinflammation is also reported to be associated in the progression of neurodegenerative diseases (Ransohoff, ) like Alzheimer’s disease (AD) (Heneka et al, ), Parkinson’s disease (Collins, Toulouse, Connor, & Nolan, ), multiple sclerosis, amyotrophic lateral sclerosis as well as other neurological disorders such as dementia, depression, schizophrenia (Block & Hong, ; Chen, Zhang, & Huang, ; Kempuraj et al, ; Smith, Das, Ray, & Banik, ). Neuroinflammation is a vast and complex mechanism but still it is crucial to understand the various neuroinflammatory mediators and their pathways, which can help in determining the effective therapies for disease associated with neuroinflammation (Shabab et al, ).…”

CSF/serum matrix metallopeptidase‐9 ratio discriminates neuro Behçet from multiple sclerosis

“…Due to its physiological role, cerebrospinal fluid (CSF) gives information on chemokines and cytokines that in part mediate neurologic autoimmune diseases 3, 4, 5. In NBD, CSF cytokines and chemokines (i.e., IL6, CXCL8, IL10, IL15, IFN γ , and TNF α ) have been correlated with pathogenesis together with Th1 and Th17 cell polarization without identifying a unique combination of cell population/soluble factors6, 7, 8; all these studies indicate a complex mechanism behind the disease.…”