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Updated: Mar 27, 2026
Author Spotlight: Investigating Physiological Functions of Vitamin A Transporters Using HPLC-Based Vitamin A Profiling
Published on: December 27, 2024
Pathways of retinoid synthesis in mouse macrophages and bone marrow cells
Haixia Niu1, Gayla Hadwiger1, Hideji Fujiwara2
1Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA and.
Abstract:
In vivo pathways of natural retinoid metabolism and elimination have not been well characterized in primary myeloid cells, even though retinoids and retinoid receptors have been strongly implicated in regulating myeloid maturation. With the use of a upstream activation sequence-GFP reporter transgene and retrovirally expressed Gal4-retinoic acid receptor α in primary mouse bone marrow cells, we identified 2 distinct enzymatic pathways used by mouse myeloid cells ex vivo to synthesize retinoic acid receptor α ligands from free vitamin A metabolites (retinyl acetate, retinol, and retinal). Bulk Kit(+) bone marrow progenitor cells use diethylaminobenzaldehyde-sensitive enzymes, whereas bone marrow-derived macrophages use diethylaminobenzaldehyde-insensitive enzymes to synthesize natural retinoic acid receptor α-activating retinoids (all-trans retinoic acid). Bone marrow-derived macrophages do not express the diethylaminobenzaldehyde-sensitive enzymes Aldh1a1, Aldh1a2, or Aldh1a3 but instead, express Aldh3b1, which we found is capable of diethylaminobenzaldehyde-insensitive synthesis of all trans-retinoic acid. However, under steady-state and stimulated conditions in vivo, diverse bone marrow cells and peritoneal macrophages showed no evidence of intracellular retinoic acid receptor α-activating retinoids, despite expression of these enzymes and a vitamin A-sufficient diet, suggesting that the enzymatic conversion of retinal is not the rate-limiting step in the synthesis of intracellular retinoic acid receptor α-activating retinoids in myeloid bone marrow cells and that retinoic acid receptor α remains in an unliganded configuration during adult hematopoiesis.
Insights
Myeloid cells use distinct pathways to create retinoic acid receptor alpha (RARα) ligands. Despite enzyme expression, RARα remains unliganded in vivo, indicating synthesis is not rate-limiting.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Retinoids and their receptors are crucial for myeloid cell development.
- In vivo retinoid metabolism in myeloid cells remains poorly understood.
Purpose of the Study:
- To investigate the pathways of retinoid metabolism in primary myeloid cells.
- To determine how retinoic acid receptor alpha (RARα) ligands are synthesized and regulated in myeloid cells.
Main Methods:
- Utilized a reporter transgene and retroviral expression of Gal4-RARα in mouse bone marrow cells.
- Analyzed enzymatic pathways for retinoic acid synthesis ex vivo using specific inhibitors.
- Examined retinoid levels in vivo under various conditions.
Main Results:
- Identified two distinct enzymatic pathways for RARα ligand synthesis in mouse myeloid cells.
- Bone marrow progenitor cells use diethylaminobenzaldehyde-sensitive enzymes, while macrophages use insensitive enzymes (Aldh3b1).
- In vivo, myeloid cells showed no intracellular RARα-activating retinoids, suggesting synthesis is not the rate-limiting step.
Conclusions:
- Myeloid cells possess distinct enzymatic machinery for retinoid synthesis.
- RARα remains largely unliganded during adult hematopoiesis, irrespective of enzyme expression or diet.
- Retinal conversion is not the rate-limiting step for RARα activation in myeloid cells.
