Objective
Following tissue injury, monocytes are recruited to the site of injury and differentiate into proinflammatory macrophages (Mφs). As wound healing progresses, these Mφs transition to an anti-inflammatory phenotype and promote tissue repair. Conversely, in type 2 diabetic (T2D) wounds the transition of Mφs to an anti-inflammatory phenotype does not occur. This causes Mφs to remain in a chronic inflammatory state, effectively preventing wound resolution. The molecular mechanisms controlling Mφ plasticity are not fully understood. Our prior work has focused on epigenetic-based mechanisms that lead to persistent expression of inflammatory genes. Specifically, we have identified that the histone acetyltransferase MOF is involved in regulating wound Mφ phenotype.
Methods
Using mice that are deficient in Mof in their monocytes/macrophages (Moff/fLyz2cre), we identified that tumor necrosis factor α receptor signaling induces Mof transcription in wound macrophages and that MOF is increased in T2D wound Mφs. We also found that MOF acetylates interferon regulatory factor 3 (IRF3) in Mφs, resulting in repression of downstream genes, including interferon β (IFNβ).
Results
This is important; we have previously shown that IFNβ expression is decreased in T2D wounds and that IFNβ is critical for the downregulation of inflammatory genes in Mφs during the transition from a proinflamatory to an anti-inflammatory phenotype.
Conclusions
Taken together, these data suggest that tumor necrosis factor α-induced Mof expression in wound macrophages regulates IFNβ via IRF3.
Article info
Publication history
Published online: June 10, 2022
22-VIRC-505-AHA-VDFootnotes
Author Disclosures: E. Barrett: Nothing to disclose; W. Melvin: Nothing to disclose; C. Audu: Nothing to disclose; F. Davis: Nothing to disclose; K. Mangum: Nothing to disclose; A. Joshi: Nothing to disclose; S. Wolf: Nothing to disclose; K. Gallagher: Nothing to disclose
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Copyright
© 2022 Published by Elsevier Inc.
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