Molecular spatial profiling of chronic intervillositis of unknown etiology implies aberrant lipid metabolism

Chronic intervillositis of unknown etiology (CIUE) is a placental inflammatory condition characterized by accumulation of maternal macrophages in the intervillous space, associated with recurrent pregnancy loss and fetal growth restriction. The pathogenesis remains poorly understood.

We performed CosMx spatial molecular imaging (6000-target RNA panel) on formalin-fixed, paraffin-embedded tissue from 14 CIUE cases (7 high-grade, 7 low-grade; mean gestational age 9 weeks), 3 SARS-CoV-2 placentitis cases, 5 normal placentas, and 1 kidney allograft rejection sample, profiling 37,203 cells across 20 cell types.

Spatial neighborhood analysis using k-nearest neighbor (k = 30) colocalization revealed progressive architectural disruption from low-grade to high-grade CIUE, characterized by loss of fibroblast-syncytiotrophoblast compartmentalization and increased macrophage clustering. Differential gene expression analysis of intervillus macrophages in CIUE compared to SARS-CoV-2 placentitis identified upregulation of genes involved in sarcoidosis and cholesterol and oxidized lipid metabolism (CYP27A1, NR1H3, CHI3L1, ALDH2, ALDH1A1). Hofbauer cells in CIUE showed a similar lipid-associated phenotype. Gene set enrichment analysis confirmed upregulation of G protein-coupled receptor signaling and FGFR pathways in CIUE macrophages, with downregulation of interferon signaling relative to SARS-CoV-2 placentitis.

These findings suggest that CIUE maternal macrophages exhibit a gene expression profile reminiscent of sarcoidosis macrophages and associated with lipid metabolism rather than viral response or classical allograft rejection, raising the hypothesis that oxidized lipid or cholesterol-related pathways may be involved in CIUE pathobiology.