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Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages

Reid Oldenburg1,2, Veronique Mayau1, Jacques Prandi3

  • 1Unité d'Immunobiologie de l'Infection, INSERM U1221, Institut Pasteur, Paris, France.

Frontiers in Immunology
|February 7, 2018
PubMed

Insights

Phenolic glycolipids (PGLs) from pathogenic mycobacteria limit nitric oxide synthase (iNOS) production in macrophages, reducing bacterial growth. PGLs also dampen toll-like receptor 4 (TLR4) signaling by reducing TRIF, affecting inflammatory responses.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Phenolic glycolipids (PGLs) are key cell wall components of pathogenic mycobacteria.
  • These molecules possess known immunomodulatory properties.
  • Their role in direct antibacterial mechanisms is less understood.

Purpose of the Study:

  • To investigate the antibactericidal activity of PGLs.
  • To elucidate the molecular mechanisms underlying PGL-mediated effects on host macrophages.
  • To explore the interaction between PGLs, complement receptor 3 (CR3), and toll-like receptor 4 (TLR4) signaling.

Main Methods:

  • Macrophage infection models with mycobacteria and purified PGLs.
  • Analysis of nitric oxide synthase (iNOS) production.
  • Investigation of toll-like receptor 4 (TLR4) signaling pathway components, including TRIF, IFN-β, and CXCL10.
  • Complement receptor 3 (CR3) dependency assays.

Main Results:

  • PGLs exhibit antibactericidal activity by downregulating iNOS production in infected macrophages.
  • This iNOS downregulation is dependent on complement receptor 3 (CR3) and induced by both bacterial and purified PGLs.
  • PGLs suppress TLR4 signaling by reducing TRIF protein levels posttranscriptionally.
  • This leads to defective production of TRIF-dependent IFN-β and CXCL10, alongside iNOS.

Conclusions:

  • PGLs possess antibactericidal properties by inhibiting macrophage iNOS production.
  • PGLs modulate host inflammatory responses by dampening TLR4-TRIF signaling.
  • TRIF is identified as a crucial mediator in the crosstalk between CR3 and TLR4 signaling pathways.
Keywords:
TLR4TRIFiNOSmacrophagesmycobacteriaphenolic glycolipids

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