PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4.

Abstract

Persistent chronic inflammation and delayed epithelialization lead to stalled healing in diabetic ulcers (DUs). PD-L1 shows anti-inflammatory and proliferative activities in healing defects, whereas its function in DU pathogenesis remains unknown. Lower levels of PD-L1 were found in DU tissues, and exogenous PD-L1 has therapeutic effects in the healing process by accelerating re-epithelialization and attenuating prolonged inflammation, which contributed to the delayed wound closure. We detected the downstream effectors of PD-L1 using transcriptional profiles and screened the interacting proteins using immunoprecipitation in combination with mass spectrometry and coimmunoprecipitation assays. The biological functions of eIF3I‒PD-L1‒IRS4 axis were tested both in vivo and in vitro. Finally, we validated the expression levels of eIF3I, PD-L1, and IRS4 in DU tissues from human clinical samples by immunohistochemistry staining. Mechanistically, PD-L1 binds to eIF3I and promotes cutaneous diabetic wound healing by downregulating IRS4. These findings identify that the eIF3I‒PD-L1‒IRS4 axis contributes to wound healing defects, which can serve as a potential therapeutic target in DUs.

• Authors: Le Kuai, Yan-Wei Xiang, Qi-Long Chen, Yi Ru, Shuang-Yi Yin, Wei Li, Jing-Si Jiang, Ying Luo, Jian-Kun Song, Bing Lu, Yue Luo, Bin Li
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 142 Issue 1 Pg. 220-231.e8 (01 2022) ISSN: 1523-1747 [Electronic] United States
• PMID: 34293353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen
• Eukaryotic Initiation Factors
• Insulin Receptor Substrate Proteins
• Intracellular Signaling Peptides and Proteins
• Irs4 protein, mouse
• TRIP-1 protein, mouse

Topics

• Animals
• B7-H1 Antigen (genetics, metabolism)
• Cell Line
• Diabetes Mellitus, Type 1 (metabolism)
• Disease Models, Animal
• Eukaryotic Initiation Factors (metabolism)
• Gene Expression Regulation
• Humans
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Keratinocytes (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Targeted Therapy
• Protein Binding
• Re-Epithelialization
• Signal Transduction
• Ulcer (metabolism)
• Wound Healing