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.

Keywords: brain; cytokines and chemokines; inflammatory mediators; mast cells; neurodegenerative diseases; neuroinflammation.

Figure 1

Mast cells in inflammatory diseases. Mast cells play a crucial role in the pathogenesis of many inflammatory diseases of various organs. Certain systemic inflammatory conditions could affect and augment neuroinflammation and neurodegeneration. Therefore, targeting mast cells represents a potentially novel approach to developing the next generation of precision guided therapeutic strategies for the treatment of inflammatory diseases. IBD, inflammatory bowel disease; CAD, coronary artery disease; BBB, blood-brain barrier.

Figure 2

Schematic diagram showing peripheral inflammatory factors and cells on neuroinflammation and neurodegeneration. Peripheral mast cell activation releases proinflammatory and neurotoxic mediators such as histamine, glia maturation factor (GMF), α-synuclein, corticotropin-releasing hormone (CRH), proteases, cytokines and chemokines. These mediators can induce neuroinflammation by inducing BBB breakdown, entering into the brain and activating glia and neurons to secrete various additional inflammatory mediators. Peripheral mast cells and T-cells enter into the brain, proliferate and secrete proinflammatory mediators that activate glia and neurons to secrete more inflammatory mediators, reduce uncoupling protein (UCP) expression, and induce neurodegeneration. Further, glia and mast cells reactivate each other in the brain through co-stimulatory molecules CD40/CD154 or inflammatory mediators such as TNF-α, IL-1β or IL-33. Mast cell tryptase acts on the neurons through PAR2. Mast cells can reactivate by their own mediators in an autocrine and paracrine manner to exacerbate inflammatory mechanisms. α-synuclein or MPP⁺ from glia/neuron or extracellular Aβ1–42 can further activate mast cells to release neuroinflammatory mediators in Alzheimer’s disease (AD) or Parkinson’s disease (PD). Additionally several inflammatory mediators from the peripheral system can alter BBB, enter the brain and activate the neuroinflammatory pathways. Inflammatory mediators released from activated microglia and astrocytes can enter into peripheral system through defective BBB; then, they can activate and recruit immune and inflammatory cells towards the inflammatory site in the brain. MC, mast cell; MCP, mast cell progenitor; TC, T-cell; PAR2, protease activated receptor-2.