Mincle Receptor Deficiency Protects Against LPS-induced Preterm Birth and Fetal Inflammatory Response Syndrome

Area of Science:

• Immunology
• Reproductive Biology
• Perinatal Medicine

Background:

• Spontaneous preterm birth (PTB) and fetal inflammatory response syndrome (FIRS) are major causes of neonatal morbidity and mortality.
• Intra-amniotic inflammation (IAI) is a key driver, but upstream immune sensors initiating this cascade are not fully understood.

Purpose of the Study:

• To investigate the role of the C-type lectin receptor Mincle in lipopolysaccharide (LPS)-induced PTB, intra-uterine inflammasome activation, and fetal/neonatal outcomes.
• To elucidate the in vivo functional significance of Mincle in mediating these processes.

Main Methods:

• LPS-induced IAI was established in wild-type and myeloid-specific Mincle knockout mice via ultrasound-guided intra-amniotic injection.
• Gestational length, neonatal survival, and postnatal growth were longitudinally assessed.
• Molecular and cellular mechanisms were analyzed using Doppler ultrasonography, flow cytometry, transcriptomics, and immunoblotting.

Main Results:

• LPS exposure caused ~50% PTB and high neonatal mortality in wild-type mice.
• Mincle deficiency completely prevented PTB, restored neonatal survival and growth, and averted fetal hyperdynamic circulation and systemic inflammation.
• Mincle was essential for decidual macrophage and neutrophil recruitment and activation, suppressing NLRP3 inflammasome activation and myometrial contractility gene expression.

Conclusions:

• Mincle acts as a critical upstream regulator of maternal-fetal inflammation, specifically within the decidua.
• Mincle governs localized inflammation, initiating PTB and fetal systemic toxicity.
• Targeting Mincle presents a promising precision medicine strategy for preventing infection-associated PTB and enhancing perinatal health.