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

Thomas, Christopher P. ORCID: https://orcid.org/0000-0001-5840-8613, 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 ORCID: https://orcid.org/0000-0002-5375-5533, Cossins, Ben C., Cardus Figueras, Ana, Carobbio, Stefania, Jones, Simon A. ORCID: https://orcid.org/0000-0001-7297-9711 and O’Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460 2025. 12/15-lipoxygenase orchestrates murine wound healing via PPARγ-activating oxylipins acting holistically to dampen inflammation. Proceedings of the National Academy of Sciences 122 (36) , e2502640122. 10.1073/pnas.2502640122

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Abstract

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 ~12 monohydroxy-oxylipins and enzymatically oxidized phospholipids (eoxPL). Alox15 deletion increased collagen deposition, stem cell/fibroblast proliferation, IL6/pSTAT3, pSMAD3, and interferon (IFN)-γ levels. Conversely, CD206 expression, F480+ cells, and MMP9 and MMP2 activities were reduced. Alox15 −/− skin was deficient in PPARγ/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 PPARγ’s anti-inflammatory brake on NLRP3/inflammasome and TGF-β 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 PPARγ response element in vitro, while in vivo, its coactivator, Helz2 , was significantly upregulated as well as several fatty acid and prostaglandin PPARγ 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 PPARγ. 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2025-09-04
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	16 September 2025
Date of Acceptance:	3 August 2025
Last Modified:	16 Sep 2025 09:30
URI:	https://orca.cardiff.ac.uk/id/eprint/181114

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