# Excessive Kynurenine Metabolism Impairs Lysosomal acidification and Triggers mtDNA Release via the AHR/CISH/ATP6V1A Axis in Decidual Macrophages Associated with Unexplained Recurrent Pregnancy Loss

## TL;DR

Excessive kynurenine metabolism in decidual macrophages disrupts lysosomal function and causes mtDNA release, contributing to unexplained recurrent pregnancy loss.

## Contribution

Identifies the AHR/CISH/ATP6V1A axis as a novel mechanism linking kynurenine metabolism to immune dysfunction in recurrent pregnancy loss.

## Key findings

- Excessive KYN-AHR activation impairs mitochondrial and lysosomal integrity in decidual macrophages.
- AHR promotes CISH transcription, leading to ATP6V1A degradation and disrupted lysosomal acidification.
- Pharmacological inhibition of AHR reduces mtDNA release and fetal loss in a mouse model of URPL.

## Abstract

Metabolic disturbances of decidual macrophages (dMφs) may contribute to the pathology of miscarriage, yet the underlying mechanisms remain poorly defined. Here, we document upregulated tryptophan metabolic pathway in dMφs from women with unexplained recurrent pregnancy loss (URPL), with increased kynurenine (KYN) levels in the decidua and elevated aryl hydrocarbon receptor (AHR) expression in dMφs. Excessive activation of the KYN-AHR axis compromises both mitochondrial and lysosomal integrity. This impairment facilitates the leakage of mtDNA into the cytoplasm and subsequent release into the extracellular space, thereby activating the cGAS-STING signaling cascade. Mechanistically, AHR directly binds to the xenobiotic response element within the CISH promoter region, promoting its transcription. The upregulation of CISH promotes the ubiquitination and degradation of ATP6V1A, disrupting lysosomal acidification and exacerbating mtDNA release. In vivo, excessive administration of KYN in pregnant mice increases the rate of embryo resorption, whereas pharmacological inhibition of AHR partially attenuates cGAS-STING pathway activation in dMφs and ameliorates fetal loss in an abortion-prone mouse model. Collectively, our findings describe a pivotal role for the AHR/CISH/ATP6V1A axis in orchestrating immune dysfunction within the decidua that may contribute to URPL, which sheds new light on the potential pathogenesis of URPL and paves the way for improving pregnancy outcomes.