Baicalin inhibits Listeria monocytogenes-induced embryonic loss through the JNK/NEK7-NLRP3/GSDMD pathway

Background: Listeria monocytogenes (LM) infections can cause embryo loss by activating the NOD-like Receptor thermal protein domain associated protein 3 (NLRP3) inflammasome at the maternal-fetal interface. Baicalin (BA), the primary active component of Scutellaria baicalensis, has been confirmed to play a critical role in fetal preservation. Nevertheless, whether BA can inhibit LM-induced embryonic loss and the potential molecular mechanism remain elusive.

Methods: In vivo, pregnant BALB/c mice were administered with BA on gestational day (GD) 0.5 for 6 consecutive days and infected with LM on GD 6.5. Pregnancy outcomes were analyzed and NLRP3 inflammasome-associated protein and Pyroptosis related indexes were measured on GD 9.5. In vitro, macrophages were treated with BA and (or) LM. NLRP3 activation, gasdermin D (GSDMD) cleavage, NIMA-related kinase 7 (NEK7)-NLRP3 binding and JNK phosphorylation were tested in cells.

Results: BA significantly reduced LM-induced mouse embryo loss, accompanied by the decrease of NLRP3 and ASC protein expression, Caspase-1 activation, GSDMD cleavage, IL-1β release and NEK7-NLRP3 interactions in uteri. In vitro experiments showed that BA alleviated LM-induced NLRP3 inflammasome-associated protein expressions, NEK7-NLRP3 interactions and JNK phosphorylation in macrophages. Interestingly, NEK7 expression levels remained unchanged in all experimental groups. Additionally, BA-mediated modulation of JNK phosphorylation could alter the expression of NLRP3 inflammasome-associated proteins and NEK7-NLRP3 interactions.

Conclusion: Our data indicated that JNK/NEK7-NLRP3/GSDMD signaling pathway plays a key role in BA-mediated alleviation of LM-induced embryonic loss, which provided a novel perspective for combating LM-associated infectious diseases.

Baicalin; Embryonic loss; JNK; Listeria monocytogenes; NEK7; NLRP3 inflammasome.