TY - JOUR
T1 - Single-cell analysis of skin immune cells reveals an Angptl4-ifi20b axis that regulates monocyte differentiation during wound healing
AU - Wee, Wei Kiat Jonathan
AU - Low, Zun Siong
AU - Ooi, Chin Kiat
AU - Henategala, Benjamin Patrana
AU - Lim, Zhi Guang Ridley
AU - Yip, Yun Sheng
AU - Vos, Marcus Ivan Gerard
AU - Tan, William Wei Ren
AU - Cheng, Hong Sheng
AU - Tan, Nguan Soon
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1038/s41419-022-04638-7
DO - 10.1038/s41419-022-04638-7
M3 - Article
C2 - 35210411
AN - SCOPUS:85125350843
SN - 2041-4889
VL - 13
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 2
M1 - 180
ER -
