HMGB1 induces unexplained recurrent spontaneous abortion by mediating decidual macrophage autophagy

The overexpression of HMGB1 at the maternal-fetal interface (MFI) is recognized as a significant factor in Unexplained Recurrent Spontaneous Abortion (URSA). This study aimed to investigate autophagy in the decidual tissues of URSA patients and to explore the relationship between HMGB1 and macrophage autophagy at the MFI in URSA.

Human decidual tissues were collected from 40 patients diagnosed with URSA and from 60 women undergoing active termination of pregnancy. Mouse models of pregnancy loss URSA and in vitro cellular models were created and then subjected to treatment with an HMGB1 inhibitor (aspirin) and an anti-HMGB1 antibody, respectively. Autophagy at the MFI was evaluated using western blot analysis, immunofluorescence assays, and transmission electron microscopy (TEM).

This study revealed a high expression of LC3B and a low expression of P62 in the decidual tissue of the URSA group. These findings were further corroborated through TEM. The localization of autophagy within macrophages indicated a significant enhancement of autophagy in the decidual macrophages of the URSA group. However, treatment with low-dose aspirin resulted in a reversal of protein expression and a reduction in autophagy. In in vitro experiments, recombinant HMGB1 was found to mediate autophagy of immortalized bone marrow-derived macrophages, which could be inhibited by an anti-HMGB1 antibody.

This study first indicates that elevated levels of HMGB1 at the MFI trigger autophagy in macrophages, thereby promoting aseptic inflammation and contributing to the onset and progression of URSA. Furthermore, low-dose aspirin has been demonstrated to protect against URSA by inhibiting HMGB1, which in turn suppresses autophagy production.