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Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.

Shatha Boukeileh1, Odai Darawshi1, Miriam Shmuel1

  • 1The School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 9112002, Israel.

International Journal of Molecular Sciences
|October 14, 2022
PubMed
Summary
This summary is machine-generated.

The unfolded protein response (UPR) pathway, particularly IRE1α, drives endoplasmic reticulum (ER) remodeling in human mast cells (MCs). This ER expansion enhances responses to Toll-like receptor 4 (TLR4) and suggests IRE1α inhibition as a strategy for allergic inflammation.

Keywords:
ER stressER-phagyTLR4UPRasthmamast cells

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The endoplasmic reticulum (ER) is crucial for protein homeostasis and function.
  • The unfolded protein response (UPR) regulates ER function and is implicated in immune cell activities.
  • Mast cells (MCs) are key players in allergic inflammation, with significant secretory functions.

Purpose of the Study:

  • To investigate the role of the UPR in mast cell activation and ER dynamics.
  • To determine the specific involvement of IRE1α in mast cell responses to FcεRI and TLR4 stimulation.
  • To explore potential therapeutic strategies targeting ER remodeling in allergic diseases.

Main Methods:

  • Utilized human cord blood-derived MCs and mouse bone marrow-derived MCs.
  • Stimulated MCs via FcεRI and assessed ER expansion and UPR activation (IRE1α, PERK).
  • Employing genetic deletion (IRE1α knockout) and pharmacological inhibition in mouse and human MCs to evaluate functional consequences.

Main Results:

  • FcεRI triggering induced ER expansion and UPR activation (IRE1α, PERK) in human MCs, but not significantly in mouse MCs.
  • IRE1α deletion in mouse MCs did not affect FcεRI-mediated degranulation or cytokine release but reduced TLR4 surface expression and LPS response.
  • Pharmacological inhibition of IRE1α in human MCs mimicked the phenotype observed in knockout mouse MCs, reducing TLR4 responses.

Conclusions:

  • Mast cell ER undergoes rapid remodeling, particularly in human cells, upon activation, which is mediated by the UPR.
  • The IRE1α-dependent ER remodeling in MCs is critical for regulating TLR4 expression and subsequent responses to LPS.
  • IRE1α inhibition presents a potential therapeutic avenue to mitigate MC hyperactivation in allergic conditions.