Oleic acid suppresses NLRP3 inflammasome activation to prevent dermal macrophage death and limit imiquimod-induced psoriasis
Psoriasis is associated with altered lipid metabolism, including reduced expression of fatty acid metabolism genes and decreased circulating oleic acid. Here we report that oral oleic acid supplementation normalized serum oleic acid levels and protected from skin thickening and epidermal hyperplasia in a imiquimod mice model of psoriasis. These effects were associated with preserved skin-resident macrophage numbers and reduced expression of key psoriasis-associated inflammatory markers. Mechanistically, imiquimod induces dermal macrophage death via NLRP3/caspase-1 inflammasome activation, while adoptive transfer of dermal macrophages attenuates psoriasiform inflammation. Oleic acid rescued macrophages from imiquimod and nigericin-induced death in vitro by suppressing NF-κB and NLRP3/caspase-1 signaling, lowering IL-1β and reactive oxygen species production, and restoring mitochondrial homeostasis, independently of TLR7. Together, our results position dermal macrophage survival as a previously unrecognized checkpoint in psoriasiform inflammation, and suggest that restoring lipid metabolic fitness, rather than solely targeting downstream inflammatory mediators, may offer an additional mechanism-based strategy to limit tissue- damaging inflammation.
Authors
- C. Henrique Serezani (ORCID: https://orcid.org/0000-0002-5363-415X)
- Beatriz Burger (ORCID: https://orcid.org/0000-0002-8666-9455)
- Marco Aurélio Ramirez Vinolo (ORCID: https://orcid.org/0000-0003-1335-760X)
- Roberta Nicolli Sagiorato (ORCID: https://orcid.org/0000-0003-0974-8130)
- Patrick Varga‐Weisz (ORCID: https://orcid.org/0000-0001-7409-8686)
- Hosana Gomes Rodrigues (ORCID: https://orcid.org/0000-0002-6122-0379)
- Ilya Andreev (ORCID: https://orcid.org/0000-0001-6414-4570)
- Vítor Rosetto Muñoz (ORCID: https://orcid.org/0000-0003-4280-6558)
- Hui Sophie Shu (ORCID: https://orcid.org/0000-0002-5317-6355)
- Yisha Liang (ORCID: https://orcid.org/0000-0001-8409-2368)
- Hernandez Moura Silva (ORCID: https://orcid.org/0000-0001-8338-8626)
- Laís Passariello Pral (ORCID: https://orcid.org/0000-0002-3008-0465)
- Gabriella Cerna (ORCID: https://orcid.org/0009-0009-2900-878X)
- Brandon Sullivan
- Jia Zhao
- Esther Midori Yabuuti (ORCID: https://orcid.org/0009-0007-0398-688X)
- Isabela Buquio Baccarin
- Nathalia Araujo
- Jose Carlos Alves Filho
- Rodrigo Angelo Martinati Bistaffa
- Charles Evavold
- Natalie Bittencourt Ramos
- Vitoria Christina Gaspar
Institutions
- University of Essex (GB)
- Universidade de São Paulo (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Vanderbilt University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Massachusetts General Hospital (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-11-01
- DOI
- https://doi.org/10.64898/2026.10.27.760067
- Primary Topic
- Psoriasis: Treatment and Pathogenesis
- Type
- preprint
Funders
- Howard Hughes Medical Institute
- Massachusetts Institute of Technology
- Vanderbilt University Medical Center
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade Estadual de Campinas