Effect of stress on brain inflammation and multiple sclerosis

this is the re-uploaded version of my previous Naver Blog Posting at 2022-05-21

Effect of stress on brain inflammation and multiple sclerosis

Cite: Karagkouni, A., Alevizos, M., & Theoharides, T. C. (2013). Effect of stress on brain inflammation and multiple sclerosis. Autoimmunity reviews , 12(10), 947-953. Link

Abstract

• MS: multiple sclerosis
  • demyelinating, autoimmune disease ← inflammation of CNS
• stress→MS: ???
• propose that neuropeptides secreted under stress: activate microglia&mast cells
  • CRH, NT(neurotnsin)
• ⇒maturation/activation of T17 autoimmune cells, disruption of BBB, T cell entry into the CNS
• ⇒promote brain inflammation, contributing to MS pathology
• novel therapeutic approach: reduction of stress & inhibition by flavonoids

Introduction

MS: autoimmune disease ← brain inflammation, demyelination, axonal loss

trigerring factors: infections, toxins, immunizations, trauma, sunlight, hormone…

stress can worsen immunity/brain inflammation → important in the pathogenesis of MS, neuropsychiatric disorders in general

Correlation between stress and MS

Human studies

Animal studies

mouse model: TMEV(Theiler’s murine encephalomyelitis virus) infection

induce EAE: experimental allergic encephalomyelitis

Involvement of microglia and mast cells

microglia play an important role in the pathogenesis of MS

MRP14, 27E10 expressed(acute stage inflammatory macrophage markers) ⇒ intense microglia infiltration in acute MS cases

hypoxia-like lesion existing MS subtype: microglial activation is prominent, precedes T-cell infiltration & demyelination

death by MS → extensive oligodendrocyte apoptosis & microglial activation in the relative absence of T-cells

Roles of Microglia

act as antigen-presenting cells for naive T-cells

expanding the number of encephalitogenic Th1 cells

produce glutamate, NO → direct effect on the death of neurons

NO: cytotoxic effect on the endothelium → contribute to BBB disruption

dying oligodendroglial cells: recruit microglia

→ induce contact-dependent oligodendroglial death in the presence of IFN-γ activation

rich source of ROS & various pro-inflammatory cytokineschemokines/proteases

Role of Microglia in the termination of the inflammatory reaction

suppress lymphocyte reactivity through NO release

strong accumulation of CD 163(+) microglia with anti-inflammatory effects was found in acute active MS lesions and at the rim of chronic active lesions

possibly involved in the resolution of the inflammation

phagocytose apoptotic T-cells(seems to be defective in MS)

in mice with EAE

microglial activation persists in chronic phase

T cell infiltrates are predominant during the acute phase of the disease

microglia participate in the pathogenesis of EAE: phagocytosing myelin + releasing TNF-α, IL-1, IL-6, chemokines

Th1 and Th2

Th1 cells, macrophages: brain infiltration

Th2 cells, mast cells: associated with allergic reactions

MS plaque at mast cell reported, could stimulate demyelination directly

Possible mechanisms to translate stress in MS risk

• actue stress permissive effect on MS exacerbation by facilitating BBB breakdown
• chronic stress lead to glucocorticoid resistance → immunce cells less responsive to regulatory control by cortisol

Stress and the HPA axis

Stress → CRH hypothalamic secretion → activate HPA(hypothalamic-pituitary-adrenal) axis

→glucocorticoids releasion → suppress immune response

In this context…

may be due to dysfunctional HPA axis because of reduced production of adrenal steroids

patients data is consistent… (absence of a normal cortisol response)

also, glococorticoid resistance development due to stress exposure can be a cause

Stress, microglia and mast cells

CRH and NT

• CRH의 pro-inflammatory effects affects brain microvessels directly → activate mast cells → BBB permeability increase
• CRH and NT which are secreted under stress synergistically stimulate mast cells → vascular permeability increase, BBB disruption
• NT stimulates mast cell secretion of VEGF(vascular endothelial GF) →increase BBB permeability
• NT induce expression of CRHR-1(CRH Receptor-1)

Stress activates microglia

• in vivo experiment evidence
• CRH: induce proliferation and TNF-α release in microglia
• microglia express NTR3 → MIP-2, MIP-1, IL-1β, TNF-α
• SP receptors detected: activation lead to the activatio of NF-κB TF
• human - microglia also produce SP → activate mast cells
• microglia respond to pro-inflammatory signals released from mast cells
• mast cell tryptase: induces microglial activation and pro-inflammatory mediator release(TNF-α, IL-6, ROS)

Conclusion

treatment?

• stress-management program
• diazepam, alprazolam

• CRH antagonist

• microglia, mast cell as therapeutic targets? ← no clinically available inhibitors
• natural flavonoids(quercetin, luteolin, apigenin): anti-oxidant, anti-inflammatory effects, suppress TNF-α, IL-6 expression and release from microglia, mast cell activation, release of cytokines
  • luteolin, quercetin: decrease myelin phagocytosed by macrophages, reduce EAE
  • luteolin: inhibits mast cell-dependent T cell activation
  • apigenin: sensitizes activated human T cells to apoptosis, inhibits auto-antigen-presenting cells necessary for the expansion and activation of Th17 cells in lupus
  • propolis(flavonoid-containing): inhibits IL-6, TGF-β induced TH17 differentiation in vitro
  • luteolin: inhibit activated peripheral blood mononuclear cells and synergistic effect with IFN-β
• luteolin may be reasonable!!