IL-4-STAT6 axis amplifies histamine-induced vascular endothelial dysfunction and hypovolemic shock

Area of Science:

• Immunology
• Molecular Biology
• Cardiovascular Research

Background:

• Severe anaphylaxis involves mast cell mediators causing vasodilatation and cardiovascular failure.
• Interleukin-4 (IL-4) synergistically enhances histamine-induced vascular endothelial (VE) dysfunction and anaphylaxis severity.
• The precise molecular mechanisms underlying IL-4's exacerbation of histamine effects remain unclear.

Purpose of the Study:

• To elucidate the IL-4-induced molecular pathways that amplify histamine-mediated VE barrier dysfunction.
• To investigate the role of IL-4 in increasing the severity of immunoglobulin E (IgE)-mediated anaphylactic reactions.

Main Methods:

• Utilized EA.hy926 VE cell line for RNA sequencing, Western blot, and Ca2+ imaging.
• Employed pharmacologic degraders and genetic inhibitors (STAT3, STAT6) in cell cultures and in vivo models.
• Analyzed histamine-induced hypovolemic shock in a mouse model.

Main Results:

• IL-4 amplified histamine-induced VE barrier dysfunction, increasing VE-cadherin degradation, calcium flux, and Src phosphorylation.
• RNA sequencing revealed IL-4 dysregulated genes related to cell proliferation and growth, enriched for STAT3 and STAT6 motifs.
• While STAT3 played a role in basal VE barrier function, IL-4 enhancement of histamine-induced dysfunction was STAT6-dependent, and STAT6 inhibition abrogated IL-4's amplification of hypovolemia.

Conclusions:

• Identified a novel IL-4/STAT6 signaling axis crucial for priming VE cells.
• This axis predisposes to exacerbated histamine-induced anaphylaxis.
• The IL-4/STAT6 pathway represents a potential therapeutic target for severe allergic reactions.