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

Spontaneous preterm birth (PTB) and fetal inflammatory response syndrome (FIRS) are severe consequences of intra-amniotic inflammation (IAI) that heavily contribute to neonatal morbidity and mortality. While the terminal pathways of labor are well characterized, the specific upstream innate immune sensors responsible for initiating the breakdown of maternal-fetal tolerance and triggering the inflammatory parturition cascade remain incompletely defined.

This study aimed to investigate the in vivo functional role of the C-type lectin receptor Mincle in mediating lipopolysaccharide (LPS)-induced PTB, localized intra-uterine inflammasome activation, and subsequent adverse fetal and neonatal outcomes.

LPS-induced IAI was established using high-resolution ultrasound-guided intra-amniotic microinjection of LPS in pregnant wild-type (Mincle^+/+) and myeloid-specific Mincle conditional knockout (Mincle^-/-) mice at 16.5 days post-coitum. We conducted longitudinal assessments of gestational length, neonatal survival, and postnatal morphometrics. Underlying molecular and cellular mechanisms were evaluated using fetal Doppler ultrasonography, flow cytometric immunophenotyping, high-throughput transcriptomics, and immunoblotting of gestational and fetal tissues.

Intra-amniotic LPS exposure triggered a ~ 50% PTB rate and profound neonatal mortality in wild-type dams. Strikingly, Mincle deficiency completely abrogated premature parturition and fully restored neonatal survival and growth trajectories. Mincle ablation prevented fetal hyperdynamic circulation and systemic fetal organ inflammation. At the cellular level, Mincle was uniquely required for the recruitment and functional antibacterial activation of macrophages and neutrophils specifically within the decidual compartment, while bulk uterine infiltration remained unaffected. This localized immune blunting in Mincle^-/- mice profoundly suppressed the transcriptional priming of Nlrp3, prevented the cleavage of Caspase-1 and maturation of IL-1β, and downregulated essential myometrial contractility genes (Gja1, Oxtr).

Mincle serves as a spatially restricted, master upstream gatekeeper of maternal-fetal inflammation. By governing localized decidual leukocyte infiltration and licensing subsequent NLRP3 inflammasome activation, Mincle drives both the mechanical onset of premature labor and fetal systemic toxicity. Therapeutically targeting the Mincle signaling axis offers a highly promising, precision-medicine strategy to simultaneously halt infection-associated PTB and safeguard lifelong perinatal health.