Anaphylactic shock depends on endothelial Gq/G11

Area of Science:

• Immunology
• Cellular Signaling
• Vascular Biology

Background:

• Anaphylaxis is a severe, multi-organ allergic reaction involving mediators like histamine and platelet-activating factor (PAF).
• These mediators often signal through G protein-coupled receptors linked to G(q)/G(11), G(12)/G(13), and G(i) proteins.
• The specific roles of downstream signaling pathways in organs during anaphylaxis remain largely uncharacterized.

Purpose of the Study:

• To investigate the role of G(q)/G(11) and G(12)/G(13) signaling pathways in endothelial cells (ECs) during anaphylactic reactions.
• To determine if targeting endothelial G protein signaling can protect against fatal anaphylaxis.

Main Methods:

• Utilized genetic mouse models with inducible Cre/loxP-mediated mutagenesis to conditionally abrogate G(q)/G(11) and G(12)/G(13) signaling in ECs.
• Administered anaphylactic mediators (histamine, PAF, LPS) and induced passive and active systemic anaphylaxis to assess outcomes.
• Monitored endothelial barrier function and nitric oxide formation.

Main Results:

• Endothelial G(q)/G(11) signaling is essential for inflammatory mediator-induced endothelial barrier opening and nitric oxide production.
• Systemic effects of histamine and PAF, but not LPS, were reduced in mice lacking endothelial G alpha(q)/G alpha(11).
• Mice with endothelium-specific G alpha(q)/G alpha(11) deficiency were protected from fatal systemic anaphylaxis, unlike those with G alpha(12)/G alpha(13) deficiency.

Conclusions:

• Endothelial G(q)/G(11)-mediated signaling is a critical driver of fatal systemic anaphylaxis.
• This pathway represents a potential novel therapeutic target for preventing or treating anaphylactic reactions.
• Targeting endothelial G(q)/G(11) signaling offers a promising strategy for managing severe allergic responses.