Mast Cells (Part 3): The Mast Cell-Glia Interaction In Chronic Inflammation
This is a multi-part series on mast cells:
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.
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
Amyotrophic Lateral Sclerosis
Autism Spectrum Disorder
Motor Neuron 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.
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
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 act like “brain glue” in the brain and regulate Blood-Brain-Barrier (BBB) integrity, axonal growth, and myelination. R
Oligodendrocytes help in myelin production as well as providing trophic support for axons and support for ATP production (via monocarboxylate transporter 1). 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
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
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
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