Prolonged IL-33 Exposure Switches the Secreted Mast Cell Cytokine Profile From Pro-Inflammatory to Pro-Tolerant

Area of Science:

• Immunology
• Allergy Research
• Cellular Biology

Background:

• Desensitization involves shifting immune responses from type 2 inflammation to immunological tolerance.
• Venom immunotherapy (VIT) with Hymenoptera venom and alum induces Interleukin-33 (IL-33) release.
• The role of mast cells (MCs) in mediating this immune response switch requires investigation.

Purpose of the Study:

• To investigate the effect of IL-33 and Hymenoptera venom on mast cell (MC) cytokine profiles under conditions mimicking venom immunotherapy (VIT).
• To determine if mast cells (MCs) contribute to the immune switch from inflammation towards tolerance during desensitization therapy.

Main Methods:

• Human mast cell lines (LAD2) and primary human skin MCs were stimulated with IL-33 and Hymenoptera venom or Compound 48/80, with or without IL-33 priming.
• Cell surface marker expression, secreted cytokines (IL-2, IL-5, IL-6, IL-13, TNF-α, TGF-β1), and c-kit phosphorylation were analyzed.
• Inhibition and stimulation of c-kit were performed to assess its role in MC responses.

Main Results:

• Unprimed MCs secreted pro-inflammatory and type 2 cytokines (IL-2, IL-5, IL-6, IL-13, TNF-α) and phosphorylated c-kit.
• IL-33 primed MCs predominantly secreted the tolerance-promoting cytokine TGF-β1, with reduced pro-inflammatory cytokines, less c-kit phosphorylation, and higher c-kit surface expression.
• Inhibition of c-kit mimicked the IL-33 priming effect, suggesting a role for c-kit signaling in MC polarization.

Conclusions:

• Prolonged IL-33 exposure, through ST2 and c-kit interactions, skews MCs towards producing tolerance-promoting cytokines during desensitization.
• Mast cells (MCs) play a significant role in directing the immune response type during Hymenoptera venom desensitization therapy.