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Peripheral Inflammation Drives TLR2 and IL‐1R1 Mediated Neurodegeneration in Parkinson’s Disease
Author(s) -
Bearoff Frank,
Johnson Marguerite,
Dhavale Dhruva,
nemacher Michael,
Kotzbauer Paul,
Kortagere Sandhya
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05585
Subject(s) - neuroinflammation , substantia nigra , neurodegeneration , tlr2 , inflammation , alpha synuclein , microglia , proinflammatory cytokine , dopaminergic , parkinson's disease , tumor necrosis factor alpha , chemistry , biology , medicine , immunology , neuroscience , dopamine , tlr4 , disease
Current evidence suggests a causal role of inflammation in the pathogenesis of Parkinson’s Disease (PD). PD is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons and the aberrant accumulation of alpha‐synuclein fibrils in Lewy bodies present in surviving dopaminergic neurons in the substantia nigra. Importantly, alpha‐synuclein fibrils can interact with toll‐like receptor 2 (TLR2) on both neurons and microglia to induce a neuroinflammatory response. Previous work has investigated the effects of pre‐existing inflammation on neurodegeneration. However, the effect of pre‐existing peripheral inflammation on alpha‐synuclein fibril induced neuroinflammation in PD has not been well understood. We hypothesize that peripheral inflammation promotes crosstalk between TLR2 and IL‐1R1 receptors when activated by alpha‐synuclein fibrils. Our preliminary results in SH‐SY5Y cells demonstrate that activation of either TLR2 or IL‐1R1 promotes synergistic interaction between the receptors leading to an increase in p‐ERK1/2 levels in a MYD88 dependent manner. In the in vivo model, prior exposure to a low dose of lipopolysaccharide (LPS) systemically increased the expression of proinflammatory cytokines such as IL‐1b and TNFα, and nuclear factor of kappa light polypeptide gene enhancer in B‐cells, alpha (IkBa) compared to animals that received saline. Treatment with alpha‐synuclein fibrils post LPS treatment significantly enhanced IL‐1b, TNFα, p‐ERK1/2 expression suggesting a synergistic effect from TLR2 and IL‐1R1 activation by alpha‐synuclein and IL‐1b respectively. In addition, these animals showed a significant increase in GM‐CSF expression compared to LPS only or saline treated animals suggesting alpha‐synuclein fibril treatment lead to an increase in infiltration of T‐cells, neutrophils and macrophages that may be causal for aberrant neuroinflammatory response in PD Support or Funding Information Drexel Coulter Foundation