12/15-lipoxygenase orchestrates murine wound healing via PPAR?-activating oxylipins acting holistically to dampen inflammation
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 am...
| Autores: | , , , , , , , , , , , , , , , , , , , |
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| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Recursos: | Centro de Investigación Principe Felipe (CIPF) |
| Repositorio: | r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF) |
| OAI Identifier: | oai:cipf.fundanetsuite.com:p4517 |
| Acesso em linha: | https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4517 |
| Access Level: | acceso abierto |
| Palavra-chave: | lipid wound oxylipin lipoxygenase |
| Resumo: | 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. |
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