HOXA10 is a Temporal Switch in Controlling Decidual Inflammation and Its Dysregulation is Associated with Early Pregnancy Loss

Abstract

Successful implantation requires precisely timed endometrial inflammation. Although an initial inflammatory burst is essential for implantation, this response must be rapidly resolved for placentation and pregnancy to progress. The mechanisms that coordinate this temporal switch remain poorly understood. Here, we identify the transcription factor HOXA10 as a key regulator of inflammatory transitions in decidual stromal cells and examine how its dysregulation contributes to implantation failure and early pregnancy loss. In mice, HOXA10 expression decreases transiently at implantation and rises again post-implantation. Silencing HOXA10 in human decidualized stromal cells induced a robust pro-inflammatory state, altered integrin and cytoskeletal gene expression, and impaired stromal substrate adhesion. In non-pregnant Hoxa10 hypomorphs, stromal cells exhibited elevated IL1β and TXNIP, activation of the NLRP3/ASC inflammasome, and dysregulation of receptivity markers. During pregnancy, persistent HOXA10 deficiency prevented the resolution of inflammation, resulting in disorganized decidua, defective placentation, infertility, or progressive reproductive decline. To assess translational relevance, we analyzed publicly available bulk and single-cell RNA-seq datasets from first-trimester human decidua and from women with recurrent pregnancy loss (RPL). Single-cell analysis revealed that HOXA10 is selectively low in inflammatory decidual stromal cell clusters, which display concordant upregulation of IL1B, PYCARD, TXNIP, and inflammasome components. Consistently, both bulk and single-cell datasets from women with RPL showed reduced HOXA10 accompanied by increased inflammatory gene expression. Overall, HOXA10 functions as a temporal switch that enables the initial inflammatory activation required for implantation and subsequently suppresses inflammation to support decidual organization, adhesion, and placentation. Loss of this switch leads to persistent decidual inflammation and is associated with pregnancy loss in both mouse models and humans. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/691844v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@ee81b6org.highwire.dtl.DTLVardef@85d84eorg.highwire.dtl.DTLVardef@13c1b6aorg.highwire.dtl.DTLVardef@12bed9b_HPS_FORMAT_FIGEXP M_FIG C_FIG