The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity.

Area of Science:

• Immunometabolism
• Innate immunity
• Molecular signaling

Background:

• ACOD1 (Immune Responsive Gene 1) produces itaconate, a key immunometabolite.
• Toll-like receptor (TLR) signaling regulates innate immune responses.
• The role of STING1 in TLR-mediated ACOD1 expression is not well understood.

Purpose of the Study:

• To elucidate the role of STING1 in mediating ACOD1 expression downstream of TLR signaling.
• To identify the molecular mechanisms linking TLR activation to ACOD1 production in myeloid cells.
• To investigate the in vivo relevance of STING1-dependent ACOD1 production in sepsis models.

Main Methods:

• Activation of STING1 using exogenous cyclic dinucleotides or endogenous mutations.
• Assessment of ACOD1 expression and itaconate production in macrophages and monocytes.
• Genetic deletion of STING1 in myeloid cells.
• Investigation of MYD88 and CGAS involvement in STING1-dependent ACOD1 expression.
• Murine models of endotoxemia and polymicrobial sepsis.

Main Results:

• STING1 activation enhances lipopolysaccharide-induced ACOD1 expression and itaconate production.
• STING1 deletion abrogates ACOD1 and itaconate production in response to TLR stimulation.
• MYD88, not CGAS, facilitates STING1-dependent ACOD1 expression by inhibiting STING1 autophagic degradation.
• STING1-MYD88 complex promotes IRF3/JUN-mediated ACOD1 gene transcription.
• Conditional deletion of STING1 in myeloid cells protects mice against sepsis.

Conclusions:

• STING1 is a critical mediator of ACOD1 expression and itaconate production in myeloid cells upon TLR signaling.
• The STING1-MYD88 complex directly links TLR4 to ACOD1 induction via IRF3/JUN.
• This pathway plays a protective role in septic shock by controlling itaconate levels.