9_InflammationReg_Microglia

Modulating Microglia Activation and Inflammation

Positive Regulation - Microglial Activation (M1)

Negative Regulation - Microglial Deactivation (M2)

Inflammatory Signals

IL-1, IL-6, TNF-a, IFN-y, ROS, NO, PG

NTs

Glutamate

Purinergic Molecules

ATP, UTP, ADP

Neuronal-Mediated

a-synuclein - secreted from dying neurons

Substance P

Serum factors

Fibrinogen

Receptor and effect

Binds to CD18, CD11b

Effect: Enhanced microglial phagocytosis

Receptor

Bind to cytokine receptors and TLRs

Receptor

mGluR2

Receptor

Puripnoceptor (P2X_ or P2Y_)

Receptors

Damage sensors on microglia

mGluR effects

Triggers release of TNF-a --> M1

High ATP

TNF-a release --> M1

P2X receptor

Low ATP

Microglial movement

P2Y receptor

Anti-inflammatory signals

TGF-B, IL-10, IL-4, IL-1RA, GCs

NTs & Neuropeptides

GABA, DA, NE, Anadamide

Neuronal-mediated

CX3CL1 (fractalkine)

CD200, CD22

HSP60

Growth factors

IGF-1, BDNF, NGF

Receptors

a-7 nicotnic receptor

B2 adrenergic receptor

GABA(B)R

Receptors

GCR, ILRs, TGF-BR

Receptors

CX3CR1

CD200R (OX-2)

CD45 (for CD22)

TREM-2

Self-regulation

Autocrine production of IL-1RA which binds to IL-1R to deactivate microglia

Microglia produce IL-10 while releasing pro-inflammatory cytokines

IL-10 effect

IL-10 negatively feedback on NFkb --> reduction in pro-inflammatory cytokines

Microlia map

Breakdown of microglia

Cannabinoids

Attenuates MGL activation

Receptor

CBD receptor on microglia

CX3CL1

Inhibition of IL1, ROS, MHCII

HSP-60

Directed phagocytosis (anti-inflammatory)

CD200L and CD22

Contact inhibition that reduces inflammation

Peripheral Fractalkine

Recruits myeloid cells to areas of inflammation (increase inflammation)

CX3CR1 KO

Have better outcomes following traumatic CNS injury because there is no myeloid cell trafficking to site of inflammation (i.e. the CNS)