Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Pace, Simona; Pergola, Carlo; Dehm, Friederike; Rossi, Antonietta; Gerstmeier, Jana; Troisi, Fabiana; Pein, Helmut; Schaible, Anja; Weinigel, Christina; Rummler, Silke; Northoff, Hinnak; Laufer, Stefan; Maier, Thorsten J.; Rådmark, Olof; Samuelsson, Bengt; Koeberle, Andreas; Sautebin, Lidia; Werz, Oliver

doi:10.1172/jci92885

Cited by 79 publications

(84 citation statements)

References 55 publications

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“…Regarding the differential expression of SPM‐biosynthetic enzymes, our results are consistent with previous studies that show that the activity of 5‐LOX and 12/15‐LOX are influenced by sex hormones 62,63 . Moreover, we observed an SS‐dependent difference in the expression of 5‐LOX and 12/15‐LOX between female NOD/ShiLtJ mice after disease onset as compared their young counterparts.…”

Section: Discussionsupporting

confidence: 91%

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

Parashar

Schulte²,

Hardt

et al. 2020

FASEB j.

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Our previous results showed that the specialized pro‐resolving mediator (SPM) Resolvin D1 (RvD1) promotes resolution of inflammation in salivary glands in non‐obese diabetic (NOD)/ShiLtJ, a mouse model for Sjögren's syndrome (SS). Additionally, mice lacking the RvD1 receptor ALX/FPR2 show defective innate and adaptive immune responses in salivary glands. Particularly, ALX/FPR2 KO mice exhibit exacerbated inflammation in their salivary glands in response to systemic LPS treatment. Moreover, female ALX/FPR2 KO mice show increased autoantibody production and loss of salivary gland function with age. Together, these studies suggest that an underlying SPM dysregulation could be contributing to SS progression. Therefore, we investigated whether SPM production is altered in NOD/ShiLtJ using metabololipidomics and enzyme‐linked immunosorbent assay (ELISA). Our results demonstrate that SPM levels were broadly elevated in plasma collected from NOD/ShiLtJ female mice after disease onset, whereas these drastic changes did not occur in male mice. Moreover, gene expression of enzymes involved in SPM biosynthesis were altered in submandibular glands (SMG) from NOD/ShiLtJ female mice after disease onset, with 5‐LOX and 12/15‐LOX being downregulated and upregulated, respectively. Despite this dysregulation, the abundances of the SPM products of these enzymes (ie, RvD1 and RvD2) were unaltered in freshly isolated SMG cells suggesting that other cell populations (eg, lymphocytes) may be responsible for the overabundance of SPMs that we observed. The elevation of SPMs noted here appeared to be sex mediated, meaning that it was observed only in one sex (females). Given that SS primarily affects females (roughly 90% of diagnosed cases), these results may provide some insights into the mechanisms underlying the observed sexual dimorphism.

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Section: Discussionsupporting

confidence: 91%

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

Parashar

Schulte²,

Hardt

et al. 2020

FASEB j.

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“…The sample size for experiments was chosen empirically based on previous studies (12,20) to ensure adequate statistical power.…”

Section: Resultsmentioning

confidence: 99%

Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome

et al. 2019

Self Cite

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Nonsteroidal anti‐inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5‐lipoxygenase (LOX), or the 5‐LOX–activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography–tandem mass spectrometry–based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on‐target actions, we found that: 1) COX or 15‐LOX‐1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP and 5‐LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3) zileuton blocks resolution‐initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4) that the 15‐LOX‐1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation‐resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.—Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.‐E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. FASEB J. 33, 6140–6153 (2019). http://www.fasebj.org

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“…The results open a new area study; that is, investigating differences in fatty acid and SPM metabolism between sexes in the context of obesity, which could have strong implications for the use of drugs that target PUFA metabolic pathways. For instance, Pace et al., recently demonstrated that females are more responsive to leukotriene biosynthesis inhibitors than males due to differences in androgens between sexes . Similarly, there are data to show that female humans are protected from inflammation induced endothelial impairments due to elevated levels of specific SPMs …”

Section: Discussionmentioning

confidence: 99%

“…For instance, Pace et al, recently demonstrated that females are more responsive to leukotriene biosynthesis inhibitors than males due to differences in androgens between sexes. 74 Similarly, there are data to show that female humans are protected from inflammation induced endothelial impairments due to elevated levels of specific SPMs. 75 The males and females had different metabolic profiles, which would influence the levels of SPM precursors.…”

Section: Discussionmentioning

confidence: 99%

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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Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Cited by 79 publications

References 55 publications

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome

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

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