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Psychopharmacology (Berl). 2019 May 22. doi: 10.1007/s00213-019-05253-9. [Epub ahead of print]

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties.

Author information

1
Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, CO, 80309, USA. david.smith3@jefferson.edu.
2
Department of Pathology, Anatomy, and Cellular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. david.smith3@jefferson.edu.
3
Centre for Clinical Microbiology, Department of Infection, UCL (University College London), London, WC1E 6BT, UK.
4
Merck Research Laboratories, MSD, Kenilworth, NJ, USA.
5
School of Bioscience, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
6
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér, 1, Debrecen, 4032, Hungary.
7
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, 80309, USA.
8
BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, 80303, USA.
9
Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, CO, 80309, USA.
10
MTA-DE "Lendület" Immunogenomics Research Group, University of Debrecen, Egyetem tér, 1, Debrecen, 4012, Hungary.
11
Department of Medicine, Johns Hopkins University, Johns Hopkins All Children's Hospital, Saint Petersburg, FL, 33701, USA.
12
Department of Integrative Physiology, Center for Neuroscience, and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA. christopher.lowry@colorado.edu.
13
inVIVO Planetary Health, of the Worldwide Universities Network (WUN), West New York, NJ, 07093, USA. christopher.lowry@colorado.edu.

Abstract

RATIONALE:

Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known.

OBJECTIVES:

Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659.

METHODS:

We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages.

RESULTS:

The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice.

CONCLUSION:

Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.

KEYWORDS:

10(Z)-hexadecenoic acid; Bacteria; Inflammation; Interleukin 6; Lipid; Macrophage; Mycobacteria; PPAR; RNA-seq; vaccae

PMID:
31119329
DOI:
10.1007/s00213-019-05253-9

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