Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue

Titos, Esther; Rius, Bibiana; López‐Vicario, Cristina; Alcaraz‐Quiles, José; García-Alonso, Verónica; Lopategi, Aritz; Dalli, Jesmond; Lozano, Juan José; Arroyo, Vicente; Delgado, Salvadora; Serhan, Charles N.; Clària, Joan

doi:10.4049/jimmunol.1502522

Cited by 93 publications

(66 citation statements)

References 35 publications

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“…We investigated if diet‐induced obesity lowered splenic SPM precursors and SPMs that may regulate B cell populations, in addition to analyses of other key PUFA‐derived metabolites . 14‐HDHA and 17‐HDHA were lowered by 2–2.5‐fold relative to controls in the spleen (Fig.…”

Section: Resultssupporting

confidence: 80%

Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

Crouch

Kosaraju

Guesdon

et al. 2018

Journal of Leukocyte Biology

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Obesity dysregulates B cell populations, which contributes toward poor immunological outcomes. We previously reported that differing B cell subsets are lowered in the bone marrow of obese male mice. Here, we focused on how lipid metabolites synthesized from docosahexaenoic acid (DHA) known as specialized pro‐resolving lipid mediators (SPMs) influence specific B cell populations in obese male mice. Metabololipidomics revealed that splenic SPM precursors 14‐hydroxydocosahexaenoic acid (14‐HDHA), 17‐hydroxydocosahexaenoic acid (17‐HDHA), and downstream protectin DX (PDX) were decreased in obese male C57BL/6J mice. Simultaneous administration of these mediators to obese mice rescued major decrements in bone marrow B cells, modest impairments in the spleen, and circulating IgG2c, which is pro‐inflammatory in obesity. In vitro studies with B cells, flow cytometry experiments with ALOX5−/− mice, and lipidomic analyses revealed the lowering of 14‐HDHA/17‐HDHA/PDX and dysregulation of B cell populations in obesity was driven indirectly via B cell extrinsic mechanisms. Notably, the lowering of lipid mediators was associated with an increase in the abundance of n‐6 polyunsaturated fatty acids, which have a high affinity for SPM‐generating enzymes. Subsequent experiments revealed female obese mice generally maintained the levels of SPM precursors, B cell subsets, and antibody levels. Finally, obese human females had increased circulating plasma cells accompanied by ex vivo B cell TNFα and IL‐10 secretion. Collectively, the data demonstrate that DHA‐derived mediators of the SPM pathway control the number of B cell subsets and pro‐inflammatory antibody levels in obese male but not female mice through a defect that is extrinsic to B cells.

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Section: Resultssupporting

confidence: 80%

Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

Crouch

Kosaraju

Guesdon

et al. 2018

Journal of Leukocyte Biology

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“…Suppressed levels of PDX and other SPMs (which were not probed for such as E-series SPMs or the PDX isomer PD1) could be driving the inability to mount effective antibody responses to influenza (61). There is precedence for the lowering of specific SPM precursors and SPMs in mouse and human obesity in select adipose tissue depots (62–64). For instance, the levels of PD1, 14-HDHA, and 17-HDHA are lowered in adipose tissue of obese mice, relative to controls, which contributes toward chronic inflammation (62, 65).…”

Section: Discussionmentioning

confidence: 99%

B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

Kosaraju

Guesdon

Crouch

et al. 2017

The Journal of Immunology

117

126

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Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B-cell function. However, there is limited information about the influence of obesity on B-cell function and underlying factors that modulate B-cell responses. Therefore, we studied B-cell cytokine secretion and/or antibody production across obesity models. In obese humans, B-cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B-cells. Furthermore, the high fat diet lowered bone marrow B-cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B-cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA3). DHA, an essential fatty acid with immunomodulatory properties, was tested since its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished antibody titers whereas the Western diet + DHA improved titers. Mechanistically, DHA did not directly target B-cells to elevate antibody levels. Instead, DHA increased the concentration of the downstream specialized pro-resolving lipid mediators (SPMs) 14-HDHA, 17-HDHA, and protectin DX. All three SPMs were found to be effective in elevating murine antibody levels upon influenza infection. Altogether, the results demonstrate that B-cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.

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“…In the future, it will be important to determine whether PGs cooperate with the broader class of bioactive lipids involved in the resolution of inflammation (40), such as those derived from ω‐3 polyunsaturated fatty acids that can stimulate phagocytic M2‐like macrophages (41). The possibility that PGs act alongside proresolving lipids would explain the counter‐intuitive observation that a gut dysbiosis‐related metabolite would exert beneficial metabolic actions in obesity similar to other beneficial mediators, such as resolvin D1 and IL‐10, which are also elevated yet dysfunctional in obesity (42). An important next step will be to ablate the induction of PG synthesis in response to microbiotaderived inflammation in vivo .…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity

et al. 2019

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Lipidomic techniques can improve our understanding of complex lipid interactions that regulate metabolic diseases. Here, a serum phospholipidomics analysis identified associations between phosphatidylglycerols (PGs) and gut microbiota dysbiosis. Compared with the other phospholipids, serum PGs were the most elevated in patients with low microbiota gene richness, which were normalized after a dietary intervention that restored gut microbial diversity. Serum PG levels were positively correlated with metagenomic functional capacities for bacterial LPS synthesis and host markers of low‐grade inflammation; transcriptome databases identified PG synthase, the first committed enzyme in PG synthesis, as a potential mediator. Experiments in mice and cultured human‐derived macrophages demonstrated that LPS induces PG release. Acute PG treatment in mice altered adipose tissue gene expression toward remodeling and inhibited ex vivo lipolysis in adipose tissue, suggesting that PGs favor lipid storage. Indeed, several PG species were associated with the severity of obesity in mice and humans. Finally, despite enrichment in PGs in bacterial membranes, experiments employing gnotobiotic mice colonized with recombinant PG overproducing Lactococcus lactis showed limited direct contribution of microbial PGs to the host. In summary, PGs are inflammation‐responsive lipids indirectly regulated by the gut microbiota via endotoxins and regulate adipose tissue homeostasis in obesity.—Kayser, B. D., Lhomme, M., Prifti, E., Da Cunha, C., Marquet, F., Chain, F., Naas, I., Pelloux, V., Dao, M.‐C., Kontush, A., Rizkalla, S. W., Aron‐Wisnewsky, J., Bermúdez‐Humarán, L. G., Oakley, F., Langella, P., Clément, K., Dugail, I. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity. FASEB J. 33, 4741–4754 (2019). http://www.fasebj.org

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Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue

Cited by 93 publications

References 35 publications

Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity

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