Neurological Recovery After Ich Is Mediated by the Aryl Hydrocarbon Receptor-Bilirubin Interplay Through Improved Erythrophagocytosis

Authors

Xiurong Zhao
Shun-Ming Ting
Guanghua Sun
Jaroslaw Aronowski

Language

English

Publication Date

2-1-2026

Journal

Journal of Cerebral Blood Flow & Metabolism

DOI

10.1177/0271678X251371375

PMID

40963261

PMCID

PMC12446277

PubMedCentral® Posted Date

9-17-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Hematoma clearance after ICH is a pro-hemostatic process aiming at repair/recovery and is achieved through microglia/macrophages (MMΦ)-mediated erythrophagocytosis. Upon the engulfment of masses of erythrocytes and toxic hemolysis products, hemoglobin and heme, phagocytes convert them to bilirubin (BrB). Bilirubin is essentially not soluble in water and when overproduced, it precipitates within the cell causing injury. Thus, keeping bilirubin soluble and at a low intracellular level is needed for proper function of MMΦ. Here, using cultured microglia (MG), we found that intracellular formation of BrB in microglia during erythrophagocytosis coincides with the activation of transcription factor AhR, and AhR target genes upregulation, including ligandin, a protein known for retention of BrB solubility, and Mrp1 known for mediating BrB efflux from the cell. Further studies showed that AhR contributed to MG' self-protection from BrB toxicity for a more efficient phagocytosis. Using mouse ICH model, we established that AhR is abundant in MMΦ located near hematoma, and that AhR agonists, ITE, used as treatment for ICH, improved both hematoma clearance and neurological recovery. In support of important role of AhR in microglia in ICH, the selective AhR-deficiency in MG in mice worsened the hematoma clearance and impaired post-ICH recovery and weakened ITE from mediating therapeutic effect.

Keywords

Animals, Receptors, Aryl Hydrocarbon, Phagocytosis, Mice, Microglia, Bilirubin, Erythrocytes, Recovery of Function, Male, Mice, Inbred C57BL, Macrophages, Basic Helix-Loop-Helix Proteins, Intracerebral hemorrhage, bilirubin, aryl hydrocarbon receptor, phagocytosis, cytoprotection

Published Open-Access

yes

Recommended Citation

Zhao, Xiurong; Ting, Shun-Ming; Sun, Guanghua; et al., "Neurological Recovery After Ich Is Mediated by the Aryl Hydrocarbon Receptor-Bilirubin Interplay Through Improved Erythrophagocytosis" (2026). Faculty, Staff and Student Publications. 5289.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5289