12/15-lipoxygenase orchestrates murine wound healing via PPARγ-activating oxylipins acting holistically to dampen inflammation

• 成果类型: Article
• 署名作者: Thomas, Christopher P.; Tyrrell, Victoria J.; Burston, James J.; Johnson, Sam R. C.; Aldrovandi, Maceler; Alvarez-Jarreta, Jorge; Inglis, Rossa; Leonard, Adam; Fice, Lydia; Costales, Jeremie; Vidal-Puig, Antonio; Protty, Majd; Guy, Carol; Andrews, Robert; Szomolay, Barbara; Cossins, Ben C.; Figueras, Ana Cardus; Carobbio, Stefania; Jones, Simon A.; O'Donnell, Valerie B.
• 署名单位: Cardiff University; Cardiff University; Cardiff University; Prince Felipe Research Center; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9386
• DOI: 10.1073/pnas.2502640122
• 发表日期: 2025-09-09
• 关键词: receptor-gamma; gene-expression; fatty-acids; arachidonic-acid; esterified eicosanoids; lipid mediators; up-regulation; in-vitro; alpha; adiponectin

摘要

12/15-lipoxygenase (12/15-LOX, Alox15) generates bioactive oxygenated lipids during inflammation, however its homeostatic role(s) in normal healing are unclear. Here, the role of 12/15-LOX in resolving skin wounds was elucidated, focusing on how its lipids act together in physiologically relevant amounts. In mice, wounding caused acute appearance of 12/15-LOX-expressing macrophages and stem cells, coupled to early generation of similar to 12 monohydroxy-oxylipins and enzymatically oxidized phospholipids (eoxPL). Alox15 deletion increased collagen deposition, stem cell/fibroblast proliferation, IL6/pSTAT3, pSMAD3, and interferon (IFN)-gamma levels. Conversely, CD206 expression, F480+ cells, and MMP9 and MMP2 activities were reduced. Alox15(-/-) skin was deficient in PPAR gamma/adiponectin activity. Furthermore, while pro-inflammatory genes were upregulated as normal during wounding, many including Il6, Il1b, ccl4, Cd14, Cd274, Clec4d, Clec4e, Csf3, Cxcl2, and miR-21 failed to revert to baseline during healing, indicating disruption of PPAR gamma's anti-inflammatory brake on NLRP3/inflammasome and TGF-beta signaling. Reconstituting Alox15(-/-) wounds with a physiological mixture of Alox15-derived primary oxylipins generated by healing wounds restored MMP and dampened collagen deposition. The oxylipin mixture activated the PPAR gamma response element in vitro, while in vivo, its coactivator, Helz2, was significantly upregulated as well as several fatty acid and prostaglandin PPAR gamma ligands. Additional inflammatory and proliferative gene networks impacted by Alox15(-/-) included Elf4, Cebpb, and Tcf3. In summary, 12/15-LOX generates abundant monohydroxy oxylipins that act together via PPAR gamma. The identification of multiple gene alterations reveals several targets for treating nonhealing wounds. Our studies demonstrate that 12/15-LOX oxylipins act in concert, dampening inflammation in vivo, revealing the need to consider lipid signaling holistically.