Hypoxia Inducible Factor 2α Promotes Tolerogenic Macrophage Development During Cardiac Transplantation Through Transcriptional Regulation of Colony Stimulating Factor 1 Receptor

Authors

Matthew DeBerge
Samantha Schroth
Fanfan Du
Xin Yi Yeap
Jiao-Jing Wang
Zheng Jenny Zhang
Mohammed Javeed Ansari
Evan A Scott
Edward B Thorp

Language

English

Publication Date

6-25-2024

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2319623121

PMID

38889142

PMCID

PMC11214057

PubMedCentral® Posted Date

6-18-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.

Keywords

Animals, Heart Transplantation, Mice, Macrophages, Basic Helix-Loop-Helix Proteins, Transplantation Tolerance, Monocytes, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Graft Rejection, Mice, Inbred C57BL, Gene Expression Regulation, Graft Survival, Male, Endothelial PAS Domain-Containing Protein 1, macrophage, transplant, tolerance

Published Open-Access

yes

Recommended Citation

DeBerge, Matthew; Schroth, Samantha; Du, Fanfan; et al., "Hypoxia Inducible Factor 2α Promotes Tolerogenic Macrophage Development During Cardiac Transplantation Through Transcriptional Regulation of Colony Stimulating Factor 1 Receptor" (2024). Faculty, Staff and Student Publications. 5524.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5524