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

  • David G. SmithEmail author
  • Roberta Martinelli
  • Gurdyal S. Besra
  • Petr A. Illarionov
  • Istvan Szatmari
  • Peter Brazda
  • Mary A. Allen
  • Wenqing Xu
  • Xiang Wang
  • László Nagy
  • Robin D. Dowell
  • Graham A. W. Rook
  • Laura Rosa Brunet
  • Christopher A. LowryEmail author
Original Investigation

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 

Abbreviations

CD

Cluster of differentiation

CNS

Central nervous system

DC

Dendritic cell

DSM-5

Diagnostic and Statistical Manual of Mental Disorders (5th ed.)

IL

Interleukin

IFN

Interferon

IRF

Interferon regulatory factor

LPS

Lipopolysaccharide

MGB

Microbiota–gut–brain

NCTC

National Collection of Type Cultures

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

PEA

Palmitoylethanolamide

PPAR

Peroxisome proliferator-activated receptor

PTSD

Posttraumatic stress disorder

RAR

Retinoic acid receptor

TGFβ

Transforming growth factor beta

TLR

Toll-like receptor

Treg

Regulatory T cell

Notes

Acknowledgements

We are grateful to Zachary D. Barger for proofreading the manuscript. We thank the University of Colorado Boulder BioFrontiers Institute Next-Gen Sequencing Core Facility, which performed the Illumina sequencing.

Author contributions

G.S.B. and P.A.I. isolated and synthesized 1,2,3-tri [Z-10-hexadecenoyl]glycerol. W.X. and X.W. developed a synthesis for 10(Z)-hexadecenoic acid and synthesized the compound. Experimental design was done by D.G.S., R.M., G.S.B., G.A.W.R., L.R.B., and C.A.L. L.N. and P.A.I designed the PPAR luciferase-based transfection assay experiments. In vivo screening and experimentation was performed by R.M. and L.R.B. In vitro experiments using freshly isolated murine peritoneal macrophages were performed by D.G.S. Transfections and reporter gene assays were performed by I.S. and P.B. RNA-seq data processing and analysis was done by D.G.S., R.D.D., and M.A.A. Experimental design and preparation of the manuscript were done by D.G.S., R.M., G.S.B., L.N., G.A.W.R., L.R.B., and C.A.L.

Funding information

This work was supported by the National Institute of Mental Health (grant number 1R21MH116263; CAL). Dr. Christopher A. Lowry is supported by the Department of the Navy, Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award (grant number N00014-15-1-2809), Department of Veterans Affairs Office of Research and Development (VA-ORD) RR&D Small Projects in Rehabilitation Research (SPiRE) (I21) (grant number 1 I21 RX002232-01), Colorado Clinical & Translational Sciences Institute (CCTSI) Center for Neuroscience (grant number CNSTT-15-145), the Colorado Department of Public Health and Environment (CDPHE; grant number DCEED-3510), and the Alfred P. Sloan Foundation (grant number, G-2016-7077). Dr. Robin Dowell is supported by NSF Career MCB #1350915.

Compliance with ethical standards

All experimental protocols were consistent with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, Eighth Edition (The National Academies Press 2011), and the Institutional Animal Care and Use Committee at the University of Colorado Boulder approved all procedures. This work was covered under CU Boulder IACUC Protocol Numbers 2134-14MAY2018 and 2361-14MAY2018-DT. The research described here was conducted in compliance with The ARRIVE Guidelines: Animal research: reporting of in vivo experiments, originally published in PLOS Biology, June 2010 (Kilkenny and Altman 2010).

Conflict of interest

Christopher A. Lowry serves on the Scientific Advisory Board of Immodulon Therapeutics Ltd. Dr. Robin Dowell is a founder and scientific advisor of Arpeggio Biosciences.

Supplementary material

213_2019_5253_MOESM1_ESM.docx (799 kb)
ESM 1 (DOCX 798 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • David G. Smith
    • 1
    • 2
    Email author
  • Roberta Martinelli
    • 3
    • 4
  • Gurdyal S. Besra
    • 5
  • Petr A. Illarionov
    • 5
  • Istvan Szatmari
    • 6
  • Peter Brazda
    • 6
  • Mary A. Allen
    • 7
    • 8
  • Wenqing Xu
    • 1
  • Xiang Wang
    • 1
  • László Nagy
    • 6
    • 9
    • 10
  • Robin D. Dowell
    • 7
    • 8
  • Graham A. W. Rook
    • 3
  • Laura Rosa Brunet
    • 3
  • Christopher A. Lowry
    • 11
    • 12
    Email author
  1. 1.Department of Chemistry and BiochemistryUniversity of Colorado BoulderBoulderUSA
  2. 2.Department of Pathology, Anatomy, and Cellular BiologyThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Centre for Clinical Microbiology, Department of InfectionUCL (University College London)LondonUK
  4. 4.Merck Research Laboratories, MSDKenilworthUSA
  5. 5.School of BioscienceUniversity of BirminghamBirminghamUK
  6. 6.Department of Biochemistry and Molecular Biology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  7. 7.Department of Molecular, Cellular, and Developmental BiologyUniversity of Colorado BoulderBoulderUSA
  8. 8.BioFrontiers InstituteUniversity of Colorado BoulderBoulderUSA
  9. 9.MTA-DE “Lendület” Immunogenomics Research GroupUniversity of DebrecenDebrecenHungary
  10. 10.Department of MedicineJohns Hopkins University, Johns Hopkins All Children’s HospitalSaint PetersburgUSA
  11. 11.Department of Integrative Physiology, Center for Neuroscience, and Center for Microbial ExplorationUniversity of Colorado BoulderBoulderUSA
  12. 12.inVIVO Planetary Health, of the Worldwide Universities Network (WUN)West New YorkUSA

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