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Title: Single-cell analysis of skin immune cells reveals an Angptl4-ifi20b axis that regulates monocyte differentiation during wound healing
Authors: Wee, Jonathan Wei Kiat
Low, Zun Siong
Ooi, Chin Kiat
Henategala, Benjamin Patrana
Lim, Ridley Zhi Guang
Yip, Yun Sheng
Vos, Marcus Ivan Gerard
Tan, William Wei Ren
Cheng, Hong Sheng
Tan, Nguan Soon
Keywords: Science::Medicine
Issue Date: 2022
Source: Wee, J. W. K., Low, Z. S., Ooi, C. K., Henategala, B. P., Lim, R. Z. G., Yip, Y. S., Vos, M. I. G., Tan, W. W. R., Cheng, H. S. & Tan, N. S. (2022). Single-cell analysis of skin immune cells reveals an Angptl4-ifi20b axis that regulates monocyte differentiation during wound healing. Cell Death and Disease, 13(2), 180-.
Project: 001325-00001
Journal: Cell Death and Disease
Abstract: The persistent inflammatory response at the wound site is a cardinal feature of nonhealing wounds. Prolonged neutrophil presence in the wound site due to failed clearance by reduced monocyte-derived macrophages delays the transition from the inflammatory to the proliferative phase of wound healing. Angiopoietin-like 4 protein (Angptl4) is a matricellular protein that has been implicated in many inflammatory diseases. However, its precise role in the immune cell response during wound healing remains unclear. Therefore, we performed flow cytometry and single-cell RNA sequencing to examine the immune cell landscape of excisional wounds from Angptl4+/+ and Angptl4-/- mice. Chemotactic immune cell recruitment and infiltration were not compromised due to Angptl4 deficiency. However, as wound healing progresses, Angptl4-/- wounds have a prolonged neutrophil presence and fewer monocyte-derived macrophages than Angptl4+/+ and Angptl4LysM-/- wounds. The underlying mechanism involves a novel Angptl4-interferon activated gene 202B (ifi202b) axis that regulates monocyte differentiation to macrophages, coordinating neutrophil removal and inflammation resolution. An unbiased kinase inhibitor screen revealed an Angptl4-mediated kinome signaling network involving S6K, JAK, and CDK, among others, that modulates the expression of ifi202b. Silencing ifi202b in Angptl4-/- monocytes, whose endogenous expression was elevated, rescued the impaired monocyte-to-macrophage transition in the in vitro reconstituted wound microenvironment using wound exudate. GSEA and IPA functional analyses revealed that ifi202b-associated canonical pathways and functions involved in the inflammatory response and monocyte cell fate were enriched. Together, we identified ifi202b as a key gatekeeper of monocyte differentiation. By modulating ifi202b expression, Angptl4 orchestrates the inflammatory state, innate immune landscape, and wound healing process.
ISSN: 2041-4889
DOI: 10.1038/s41419-022-04638-7
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Biological Sciences 
Rights: © 2022 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
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