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Front Immunol. 2018 Jan 19;9:2. doi: 10.3389/fimmu.2018.00002. eCollection 2018.

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

Author information

1
Unité d'Immunobiologie de l'Infection, INSERM U1221, Institut Pasteur, Paris, France.
2
Université Paris Diderot, Paris, France.
3
Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
4
Unité de Biologie et Génétique de la Paroi Bactérienne, Institut Pasteur, Paris, France.
5
INRA, UMR 1282 Infectiologie et Santé Publique, Nouzilly, France.
6
Université François Rabelais, Tours, France.

Abstract

Phenolic glycolipids (PGLs) are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS) in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR)4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-β (TRIF) protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-β and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.

KEYWORDS:

TLR4; TRIF; iNOS; macrophages; mycobacteria; phenolic glycolipids

PMID:
29403489
PMCID:
PMC5780341
DOI:
10.3389/fimmu.2018.00002
[Indexed for MEDLINE]
Free PMC Article

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