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The delayed kinetics of Myddosome formation explains why amyloid-beta aggregates trigger Toll-like receptor 4 less

Bing Li1,2, Prasanna Suresh1,2, Jack Brelstaff3

  • 1Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.

Elife
|June 12, 2024
PubMed

Insights

The Myddosome, an immune signaling platform, forms faster and disassembles quicker when triggered by LPS than amyloid-beta (Aβ) fibrils. This difference in Myddosome dynamics explains the varied TLR4 signaling responses to these triggers.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • The Myddosome is a critical innate immune signaling platform involving MyD88 and IRAK proteins.
  • Toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS) or amyloid-beta (Aβ) aggregates leads to pro-inflammatory cytokine production.
  • The differing magnitudes and durations of TLR4 signaling responses to LPS versus Aβ are not well understood.

Purpose of the Study:

  • To investigate the dynamic formation and disassembly of Myddosomes in response to different TLR4 agonists.
  • To elucidate the reasons behind the distinct signaling kinetics observed with LPS and Aβ fibrils.

Main Methods:

  • Live macrophage imaging using 3D rapid light sheet microscopy to track Myddosome formation.
  • Super-resolution imaging of fixed macrophages to determine Myddosome size over time.
  • Utilized local delivery of TLR4 agonists (LPS and sonicated Aβ fibrils) to the cell surface.

Main Results:

  • Myddosomes formed significantly faster upon LPS stimulation (80s) compared to sonicated Aβ fibrils (372s).
  • Myddosome mean lifetimes were shorter with LPS (170s) than with Aβ fibrils (220s).
  • Both triggers formed Myddosomes ranging from 50-500 nm, with smaller ones prevalent at early time points.

Conclusions:

  • The multivalency of Aβ fibrils promotes the formation of larger, slower-forming, and longer-lived Myddosomes compared to LPS.
  • These Myddosome size and stability differences explain the less efficient TLR4 signaling triggered by sonicated Aβ fibrils.
  • Myddosome dynamics influenced by aggregate properties may be a general mechanism in protein aggregate-mediated signaling.
Keywords:
MyddosomeTLR4amyloid betafluorescence imagingimmunologyinflammationnone

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