10_M1_M2 | Myndbook

M1 vs M2 microglia/macrophages

M2

M1 - classical activation

Stimulated by

IFNy + TNF-a

Cytokine sources

CD4/Th1, CD8, NK cells --> IFN-y

Microglia/macrophage --> TNF-a

Response to activation

Inflammatory

Cytokines released

IL-1B, TNF-a, IL-6

Function

Microbicidial activity

Function

ROS and pro-inflammatory cytokine release

Function

Complement-mediated phagocytosis

Also stimulated by..

TNF-a + LPS & TLRs

M1 phenotypes?

M1 response is context dependent

Classic pheontypes: low IL-10

- can produce high IL-10 during peripheral immune challenge

EAE model

M1 is pathological as it responds to fibrinogen leaking into brain and strips away myelin

Classic M1 function

Viral/bacterial clearance using inflammatory cytokines & ROS

Can lead to..

BBB permeability, tissue death, demyelination

Models of Activation

Model 1: Linear model

Specific cytokines activate M1 vs M2

Model 2: Spectrum model

Tries to explain discrepancies in factors being present during both M1 and M2 activation

Model 3: Developmental Model

Develop from M0 (surveying) to M1 to M2 back to M0

- transition states exist between each state in which both markers are expressed

Wrong

Too many factors to determine specifics, and microglia can respond to similar factors differently based on environment

M2c

Classical Deactivation

M2b

Inflammatory and Homeostatic

M2a

Alternative Activation

Stimulating factors

IL-4

Functions:

Tissue repair

Angiogenesis

Clean up debris w/o inflammation

Wound healing

reduce Pro-inflammatory cytokines

release of neurotrophins

Stimulating factors

Antibody + antigen and IL-1B or LPS

Phenotype/Function

High IL-1B and IL-10

- shows both inflammatory and homeostatic role (anti-inflame) of M2b

Phenotype/Function

Anti-inflammatory via IL-10, IL-4, and SOCS

Main function:

Inhibit Th1/M1 response

Stimulating factors

IL-10, TGF-B, and GCs

Via

CD4/Th2, neutrophils

Via

B cells provide immune complex

MGL/Mac provide IL-1B

Via

MGL/mac and regulatory T-cell --> IL-10

Astrocytes and MGL/MAC --> TGF-B

HPA axis --> GCs

Phenotype

High arginase, mannose receptor

Ym-1 + low NO

Consequence of main func.

Impaired clearance of bacteria/virus

T-cell anergy

Other processes that M1/M2 are involved in

Synaptic Pruning

Description

Axonal growth/Neurogenesis

Description

LTP

Description

Neuroprotection

Description

Cognition

Description

Sickness Behavior

Description

Repair

Description

Phenotype Plasticity

M1 can switch to M2 in vivo based on factors present (and vice-versa)

Aging

Description

M1 or M2

M1 necessary synaptic engulfment

M2 necessary to make sure not too much pruning

(Fractalkine)

M1 or M2

M1 provides IL-1B which promotes neurogenesis and axonal growth after injury

M1 or M2

M1 provides TNF-a which promotes AMPAR localization on dendrites for LTP

M1 or M2

Exogenous M1 IFN-y can buffer glutamate and reduce neurotoxicity and improve neuroprotection

M1 or M2

M2 provides IL-4 which promotes learning and memory

- Drives BDNF and reduces M1

M1 or M2

M1 causes sickness behavior

M1 inhibition reduces it

M2 IL-4 before LPS improves sickness behavior

M2 IL-4 administered w/ LPS (causes sickness behavior) prolonged state

So which one is good? Most likely M2, but not 100%

M1 or M2

M2 arginase helps stimulate neurite growth

M2 associated with high CCL2 (monocytes) and IL-1B at damage site

Overall good for repair, but not anti-inflammatory

SCI

M1 TLR2 promote neurite growth after SCI

Prolonged M1 TLR2 lead to neuronal death

Role of Arginase

Help produces polyamines that support neurite growth

Polyamines also recruit monocytes (CCL2) by acting on astrocytes to areas of damage

Phagocytosis

M1 - dead/dying cells, clear debris

M2 - apoptotic cells, reduces inflammation

(TREM 2)

Shift towards M1

More MHCII, more inflammatory, produce more M1 cytokines

Prolonged sickness behavior

Shift Away M2

Downregulation of CX3CRI - anti-M2 receptor

Impaired IL-4RA upregulation

???

Most likely correct