NEUS 609 - Microglia

macroglia

• CNS = astrocytes, oligodendrocytes, ependymal cells (line ventricles)

• PNS = Satellite cells, Schwann cells

microglia

• CNS: microglia (derived from yolk sac precursor)

• PNS: macrophages (derived from bone marrow aka MYELOID precursors)

glia

___ provide physical, metabolic, and trophic support for neurons

endodermal, ectodermal

microglia have an ___ embryological origin compared to the rest of the nervous system which has an ___ embryological origin

first

microglia are the __ type of glia produced during development

adulthood

microglia continue to divide in ___ and thus are the source of most neural cancers

quiescent

name of the resting morphology that is ramified

amoeboid

name of activated morphology triggered by injury, pathogens or misfolded proteins

• small, oval/rounder, kind of bacteria-looking

uniform

In a healthy CNS, the distribution of microglia is ___ meaning that the cell bodies are separate but cytoplasmic processes can connect and communicate while evenly covering the brain region.

erythromyeloid stem cells

microglia come from an extraembryonic yolk sac stem cell aka ___

• they NEVER inhabit the bone marrow

• undergo SELF-RENEWAL

parenchyma

functional part of an organ

microglia tend to be found in the CNS proper brain tissue aka the brain ___, while macrophages tend to be found in CNS connective tissues & perivascular space.

• parenchyma can be invaded by macrophages upon injury

glymphatic system

aka glial-lymphatic system

para-arterial fluid with perivascular space flows through glia and interstitial space as CSF is exiting via para-venous space.

pathogen surveillance

microglia scan CSF and ISF in glymphatic system for ___

• depending on pathogen, microglia OR astrocytes are activated first and then release signal activating the other.

neuroimmune regulation

the main function of microglia is ____ aka the brain immune system relies on microglia for defense against pathogens and foreign bodies based on the restricted access model (BBB restrict access to the brain to most other immune cells, but T cells can sometimes unzip parts of BBB to get across if they want to).

innate immnunity

microglia are part of ____

EXPEDITOUS immunity, which is present at birth and includes receptors, cellular responses, physical and anatomical barriers. Recognize and neutralizes KNOWN pathogens.

• includes mechanisms like phagocytosis

• IMMEDIATE response that can trigger adaptive immunity

adaptive immunity

PRECISE immunity which is programmable/customizable. recognize and neutralize NOVEL pathogens.

• DISCRIMINATE BETWEEN SELF & NON-SLEF

• primary response (slowest response)

• secondary response (memory response)

primary response

part of adaptive immunity

slow and precise response, deliberate.

secondary response

part of adaptive immunity

memory response, aka repeat exposure, more rapid and robust than other type of responses

pathogen-associated molecular pattern

aka PAMPS

molecular components unique to microbe

• LPS on gram negative bacteria

• peptidoglycan on gram positive bacteria

• dsRNA of some viruses

damage-associated molecular patterns

aka DAMPS

damaged host molecules triggering innate immune response (any unfamiliar host cell characteristic)

pattern recognition receptors

aka PRR

Receptors recognizing PAMPS and DAMPS

• each PRR has its own unique response

• includes toll-like receptors

sentinels

resting microglia with quiescent morphology whose role is surveillance

agressors

activated microglia with an amoebae morphology whose role PRRs activation, neurochemical and pro-inflammatory signals release.

altruistic agressors

overactivated microglia which die in the process of eliminating pathogens

• suicide microglia

major histocompatibility complexes

aka MHCs

discriminate between self and non-self

MHCI

1- identify INTRACELLULAR antigens inside cell as it’s a non-phagocytic process

2- Move antigen to proteosome and degrade/digest it using peptidases

3- amino acids taken into the ER and interesting sequences associated with ___

4- ___ pushed to the surface attached to interesting foreign sequence and given to CD8 naive cytotoxic T-cells

In all nucleated cells and usually recognizes DAMPS

MHCII

1- recognizes and phagocytoses EXTRACELLULAR antigens

2- pack antigens in endosome with proteases to digest/degrade them

3- Identifying amino acid sequences attach to ___ from ER and are pushed to the surface

4- recognized by CD4 naive helper T cells

Only present in antigen presenting cells (APCs) and usually deal with PAMPs

cytokine, differentiation

helper T cells response involves the release of ___ and the ___ of more T cells and B cells.

perforin, granzyme

cytotoxic T cells response involves death of infected cells by ___ and ___ proteins

T cell activation

1- TCR (T cell receptor) binding which activate Th cells via MHCII

2- Co-stimulation: B7 on antigen presenting cells (APCs) interact with CD28 on Th cells

3- Specific cytokines: such as IL-B2 promote Th cells proliferation (clonal expansion) and differentiation

sustained

__ microglia activation = neurodegeneration/spiraling inflammation

• neurotoxic factors released by activated microglia to kill pathogens damages neurons which release more cytokines and activates more microglia

Functions of microglial phagocytosis

• developmental and plasticity-induced removal of synapses

• developmental removal of neuronal precursors

• removal of stressed neurons

• removal of live neutrophils

• removal of live glioma cells

Diverse & with both positive and negative impacts

On signal

• glutamate (soluble)

• ATP (soluble)

• cytokines (soluble)

• TREM2 (membrane bound)

off signal

• TGF-B (soluble)

• GABA (soluble)

• BDNF (soluble)

• NGF (soluble)

M0

Resting phenotype

• ramified/quiescent morphology

• surveillance

• HIGH PRR expression

M1

Activated CYTOTOXIC phenotype

• HIGH inflammation

• HIGH nitric oxide synthase

• HIGH pathogens elimination

• HIGH reactive oxygen species (ROS) and RNS from L-arginine

• HIGH cytokines

• HIGH MHCII expression

M2

Activated repair/rebuilding phenotype

• HIGH clean up

• HIGH arginase L-arginine use shifts to ornithine cycle & production of polyamides involved in repair

• HIGH phagocytosis

• HIGH scavenger receptors

dysfunctional

___phenotype

• LOW surveillance

• LOW PRR

• LOW cytotoxicity

• LOW repair

switch

macrophages and microglia can ___ phenotype, but it is not an easy process & it is highly regulated.

astrocytes

microglia are like ___ in the way that they look and preserve NT balance and stay in contact with all parts of tripartite synapse

• express NT receptors (CB2, NMDA, AMPA etc.)

• produce neurotrophic factors like BDNF

• produces cytokines

• release glutamate

partial phagocytosis

microglia also prune synapses via ____ to ensure synaptic development and plasticity

• very selective

• signal on membrane of weak synapses

pathology

neuropathic pain accompanied by altered microglial and to a lesser extent astroglial signaling

• glia tend to stay turned on in neuropathic conditions

acute pain microglial mechanism

1- painful stimuli overexcite primary sensory neuron leading to increased release of capase-6

2- capase-6 triggers p38 phosphorylation in microglia

3- microglia release TGF-alpha, IL-1B, IL-18, and prostaglandins

4- TGF-alpha activates TNFR-1/2 which increases ERK and activates TRPV1 to release glu

5- glutamate activates NMDA and AMPA inhibiting potassium channels = pain

TNFR > P-ERK > P-CREB > altered gene expression > pain

aging

microglia lose function and/or become dysfunctional with ___

• slower response

• inappropriate response

• eventually apoptotic

TREM2

triggering receptor expressed on myeloid cells & key regulator of microglial activation

• integral membrane domain + tethered soluble fragment

• cleavage of tethered segment leads to signal response termination

• mutations are risk factor for Alzheimer’s disease

• increased amyloidgenesis with LOSS of ___