T cell-derived soluble glycoprotein GPIbα mediates PGE₂ production in human monocytes activated with the vaccine...

Area of Science:

• Immunology
• Vaccinology
• Molecular Biology

Background:

• Vaccine adjuvants activating pattern recognition receptors (PRRs) can induce prostaglandin E2 (PGE2) release, leading to fever and inflammation.
• Muramyl dipeptide (MDP) is a NOD2-activating adjuvant analog of microbial products.
• The precise mechanism of MDP-induced PGE2 production in human monocytes requires further elucidation.

Purpose of the Study:

• To investigate the mechanism of PGE2 production by human monocytes activated with MDP.
• To identify co-factors from T cells that influence MDP-induced inflammatory responses.
• To elucidate the signaling pathways involved in MDP-mediated PGE2 and cytokine production.

Main Methods:

• Human monocytes were activated with MDP alone or in combination with T cell-conditioned medium (Tc CM).
• PGE2, IL-1β, and IL-6 levels were measured using mass spectrometry and immunoblotting.
• Antibody-mediated blockade of glycoprotein Ibα (GPIbα) and its receptor Mac-1 integrin was employed.
• Experiments were conducted in wild-type and Mac-1 knockout (KO) mice.

Main Results:

• MDP alone did not induce PGE2 production in human monocytes.
• MDP combined with Tc CM significantly increased PGE2, IL-1β, and IL-6 secretion.
• Glycoprotein Ibα (GPIbα) in Tc CM was identified as a key costimulatory factor.
• Blockade of GPIbα or Mac-1 inhibited PGE2 and cytokine release; recombinant GPIbα enhanced it.
• Mac-1 deficiency reduced COX2 mRNA abundance in vivo following MDP administration.

Conclusions:

• MDP-induced PGE2 and proinflammatory cytokine production by monocytes requires cooperation between NOD2 signaling and T cell-derived GPIbα activation of Mac-1.
• This finding reveals a novel mechanism contributing to adjuvant-induced inflammatory responses and fever.
• Targeting the GPIbα-Mac-1 pathway could mitigate adverse inflammatory effects of certain vaccine adjuvants.