Resolvin D1 and Its Precursor Docosahexaenoic Acid Promote Resolution of Adipose Tissue Inflammation by Eliciting Macrophage Polarization toward an M2-Like Phenotype
Abstract
We recently demonstrated that ω-3-polyunsaturated fatty acids ameliorate obesity-induced adipose tissue inflammation and insulin resistance. In this study, we report novel mechanisms underlying ω-3-polyunsaturated fatty acid actions on adipose tissue, adipocytes, and stromal vascular cells (SVC). Inflamed adipose tissue from high-fat diet-induced obese mice showed increased F4/80 and CD11b double-positive macrophage staining and elevated IL-6 and MCP-1 levels. Docosahexaenoic acid (DHA; 4 μg/g) did not change the total number of macrophages but significantly reduced the percentage of high CD11b/high F4/80-expressing cells in parallel with the emergence of low-expressing CD11b/F4/80 macrophages in the adipose tissue. This effect was associated with downregulation of proinflammatory adipokines in parallel with increased expression of IL-10, CD206, arginase 1, resistin-like molecule α, and chitinase-3 like protein, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. This shift was confined to the SVC fraction, in which secretion of Th1 cytokines (IL-6, MCP-1, and TNF-α) was blocked by DHA. Notably, resolvin D1, an anti-inflammatory and proresolving mediator biosynthesized from DHA, markedly attenuated IFN-γ/LPS-induced Th1 cytokines while upregulating arginase 1 expression in a concentration-dependent manner. Resolvin D1 also stimulated nonphlogistic phagocytosis in adipose SVC macrophages by increasing both the number of macrophages containing ingested particles and the number of phagocytosed particles and by reducing macrophage reactive oxygen species production. No changes in adipocyte area and the phosphorylation of hormone-sensitive lipase, a rate-limiting enzyme regulating adipocyte lipolysis, were observed. These findings illustrate novel mechanisms through which resolvin D1 and its precursor DHA confer anti-inflammatory and proresolving actions in inflamed adipose tissue.
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Annexin A1 and SPMs such as LXA4, RvD1 and RvE1 drive macrophage polarization toward an M2-like or intermediate phenotype.
“Annexin A1, which is expressed in tissue-resident effector cells including macrophages and mast cells158, and several members of the SPM family, such as LXA4, RvD1 and RvE1, stimulate macrophage polarization towards an M2-like or intermediate phenotype114,159,160.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [160]
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- Authors
- Titos, E., Rius, B., González-Périz, A., López-Vicario, C., Morán-Salvador, E., Martínez-Clemente, M., Arroyo, V., & Clària, J.
- Affiliations
- Hospital Clínic de Barcelona (ES)
- Department of Biochemistry and Molecular Genetics, Hospital Clinic, Center Esther Koplowitz, August Pi i Sunyer Biomedical Research Institute , 08036 Barcelona ,
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Corresponding author
- Titos, Esther
- Rius, Bibiana
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-11
- Volume
- 187
- Issue
- 10
- Pages
- 5408-5418
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1889359478
- Cited by
- 412
- References
- 44
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 13 · 2023: 21 · 2022: 24 · 2021: 26 · 2020: 40 · 2019: 29 · 2018: 25 · 2017: 35 · 2016: 34 · 2015: 42 · 2014: 34 · 2013: 39 · 2012: 21
- FWCI
- 28.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- resolvin D1, docosahexaenoic acid, omega-3 polyunsaturated fatty acids, adipose tissue inflammation, macrophage polarization, M2 macrophages, stromal vascular cells, obesity, insulin resistance, arginase-1, Th1 cytokines, phagocytosis, reactive oxygen species, specialized pro-resolving mediators, high-fat diet
- MeSH terms
- Adipose Tissue, Animals, Disease Models, Animal, Docosahexaenoic Acids, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Random Allocation, Signal Transduction, Immunophenotyping, Cell Polarity, Inflammation Mediators, Mice
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