HMGB1 orchestrates uterine macrophage trafficking to safeguard embryo implantation

A reciprocal communication between the implantation-competent blastocyst and the receptive uterus is essential to implantation. Blastocyst implantation is considered to be a regulated proinflammatory response in the uterus, however the underlining mechanism remains elusive. Here, we provide genetic evidence that High-mobility group protein Box-1 (HMGB1), expressed in uterine cell nuclei, restricts inflammatory responses during the periimplantation period. Conditional deletion of uterine Hmgb1 by using a Pgr-Cre driver (Pgr cre/+ Hmgb1 f/f ) shows substantial infertility because of defective implantation and subsequent adverse ripple effects. These mice accumulate and retain an increased number of macrophages in the stroma on day 4 of pregnancy with a unique enrichment of macrophages in the stroma encircling the blastocyst on day 5, evoking inflammatory responses. These results are in contrast to previous findings that HMBG1 is an internal alarmin. In search for the mechanism, we found that Hmgb1-deleted stromal cells show reduced activation of PR and decreased Hoxa10 expression, providing evidence that PR and Hoxa10 mediated regression of inflammation is mediated by HMGB1. In addition, levels of two macrophage attractants CSF1 and CCL2 are elevated in the stroma and in vitro studies show that CSF1 specifically attracts macrophages which is abrogated if challenged with a CSF1 receptor antagonist. The results suggest that Hmgb1 contributes to successful blastocyst implantation by regulating macrophage trafficking in the stroma to prevent excessive inflammatory responses.