Sustained STING-IRF7 signaling aggravates LPS-induced endometrial inflammation via excessive neutrophil extracellular traps generation

TL;DR

This study shows that sustained STING-IRF7 signaling worsens endometrial inflammation by increasing neutrophil extracellular traps, suggesting targeting this pathway could help treat chronic endometritis.

Contribution

The study identifies a novel STING-IRF7-driven mechanism linking excessive NETs formation to chronic endometrial inflammation.

Findings

STING deficiency reduces NETs formation and myeloperoxidase activity in LPS-induced endometritis.

The STING-IRF7 axis regulates CD11b and LCN2, which promote neutrophil recruitment and NETosis.

STING deficiency reprograms the endometrial immune environment and restores HOXA10 expression.

Abstract

The stimulator of interferon genes (STING) is a central mediator of innate immune sensing and represents a critical regulator of chronic inflammation. Upon persistent infection, excessive neutrophil activation leads to the formation of neutrophil extracellular traps (NETs) that damage the tissues. However, the mechanism by which STING signaling regulates NETs formation under chronic inflammatory conditions remains poorly understood.

In this study, using LPS-induced murine endometritis models in wild-type and STING-deficient mice, we demonstrated that STING deficiency significantly suppressed myeloperoxidase activity, and diminished NETs formation.

We identified neutrophil surface molecular CD11b as a key downstream target of STING, whose expression was transcriptionally regulated via IRF7. Furthermore, the STING-IRF7 axis was found to drive lipocalin-2 (LCN2) expression, which acted through its receptor MC4R to upregulate intracellular adhesion molecule-1 (ICAM-1), thereby facilitating neutrophil recruitment and NETosis during LPS stimulation. The role of this pathway was validated both in vitro using isolated neutrophils and in vivo using Lcn2-/- mice. Moreover, STING deficiency reprogramed the endometrial immune microenvironment by reducing inflammatory infiltration and restoring receptivity transcription factor homeobox A10 (HOXA10).

Our findings revealed a novel mechanism in which the STING-IRF7 pathway exacerbated endometrial inflammation and tissue damage by coordinately upregulating CD11b and activating the LCN2-ICAM-1 axis. Consequently, targeting the STING signaling pathway may offer a promising therapeutic strategy for chronic endometritis.

Figures