Mast Cells (Part 3): The Mast Cell-Glia Interaction In Chronic Inflammation

This is a multi-part series on mast cells:

1. Mast Cells (Part 1): Stabilize Mast Cells And Remove Brain Fog

2. Mast Cells (Part 2): Mast Cells And Cancer

3. Mast Cells (Part 3): The Mast Cell-Glia Interaction In Chronic Inflammation

In this post we will focus on the mast cell-glia (microglia, astrocyte, oligodendrocyte) interaction with our body and how they contribute to chronic inflammatory diseases such as CIRS and SALI.

Basics

The Central Nervous System (CNS) can communicate to the immune system and mediate multiple inflammatory responses.

While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral and central nervous systems: R

• Alzheimer Disease

• Amyotrophic Lateral Sclerosis

• Autism Spectrum Disorder

• Depression

• Fibromyalgia

• Ischemia

• Motor Neuron Disease

• Multiple Sclerosis

• Neuropathic Pain

• Parkinson Disease

• Traumatic Brain Injury

The core problem with inflammation is not how often it starts, but how often it fails to subside. R

Microglia (the brain's main immune guardians) and mast cells, along with astrocytes (and possibly even oligodendrocytes) are the three biggest players in chronic inflammation.

They all play a key role by regulating our responses to infection, inflammation, and reactions to stress or trauma.

Just looking at these 3 parts individually does not provide a whole picture of SALI but does highly represent the chronic inflammatory response.

Glia

Microglia provide “immunosurveliance” of the brain, constantly surveying their environment in preparation for insult or injury. R

When they are activated, they eat up cellular debris and then present antigens to T cells and release cytokines/chemokines. R

These processes are normal and used to keep homeostasis in the brain, such as: R

• Engulf synaptic material

• Initiate synaptic pruning

• Regulate cell death

• Regulate neurogenesis

M1 Vs M2 State Microglia

Microglia play a role in plasticity and will either be in a M1 (classic/pro-inflammatory) or M2 (alternative polarization/neuroprotective) state. R

Astrocytes

Astrocytes act like “brain glue” in the brain and regulate Blood-Brain-Barrier (BBB) integrity, axonal growth, and myelination. R

Oligodendrocytes

Oligodendrocytes help in myelin production as well as providing trophic support for axons and support for ATP production (via monocarboxylate transporter 1). R

Mast Cells

Mast cells play a multitude of functions and generally act as environmental sensors. R

When activated they can release a numerous amount “packaged” molecules such as numerous vasoactive, neurosensitizing and pro-inflammatory mediators, which include biogenic amines (histamine, serotonin), cytokines, proteolytic enzymes (e.g., chymase, tryptase, acid hydrolases, among others), lipid metabolites (prostaglandin D2, leukotriene C4, platelet-activating factor), ATP, neuropeptides, nerve growth factor (NGF), vascular endothelial growth factor (VEGF) and nitric oxide. R R

Mast cells can also induce T cell activation, proliferation, and cytokine secretion. R

How Mast Cells And Glia Create Strong Bonds

The more inflammation happens, the more that mast cells and glia communicate and create stronger bonds/crosstalk.

This mast cell-glia/glia-glia crosstalk can be mediated via: R

• Antigen-presenting cells (CD40/CD40L/RhoGTPase/MAPK/NF-kb/STAT1) R

• Central sensitization (BDNF hypersensitivity/ATP/P2/P2X4/Ca2+/NF-κB/PAR2/TNF-α/IL-6/IL-33/IL-13/CCL2) R

• Complement system (ie C5a/CD88; C3/C3a/NF-kb) R R

• PAMPs (TLR2/TLR4/CCL5/RANTES/IL-6/CCL5) R

How Neuroinflammation Causes Inflammaging

Aging is associated with elevated levels of circulating cytokines and pro-inflammatory markers, and age-related changes in the immune system often referred to as “immunosenescence” or “inflammoaging”. R R

For example, infections have shown to cause inflammoaging of the hippocampus, a possible pathology of Alzheimer’s. R

Senescent (old, but undead) microglia are present in aging - they are primed to activation, but resistant to regulation. R R R

These “primed” kind of glia are extra sensitive to a secondary inflammatory stimulus, thus leading to an exaggerated inflammatory response, and may contribute to the inflammaging as seen in CIRS and SALI. R

For example, Lipopolysaccharides (LPS) cause endotoxemia (sepsis - showing a multipolar cytokine storm similar to CIRS), and LPS are able to prime the glia and mast cells. R

Having chronic levels of even low LPS can cause a persistent state of low-grade inflammation which is associated with innate immune “programming” or “memory” (ie altered BBB, cognitive dysfunction, pain, etc). R R

Top Ways To Stop Mast Cell-Glia Inflammation

Top Ways To Stop Mast Cell-Glia Inflammation:

• Palmitoylethanolamide (PEA) R

• PeaLut R