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.
Highlights
Phenolic glycolipids (PGLs) are polyketide synthase products that are only synthesized by a subset of pathogenic mycobacteria, including the W-Beijing family of Mycobacterium tuberculosis strains and Mycobacterium leprae [1,2,3]
To see if PGLs affect nitric oxide (NO) production in activated macrophages, we compared intracellular levels of induce nitric oxide synthase (iNOS) in Bone marrow-derived macrophage (BMDM) infected with recombinant BCG expressing PGLs, or PGL-deficient BCGs as control, in the presence of IFN-γ
We report in the present work that exposure of macrophages to mycobacterial PGLs affects the integrity of their TLR4 signaling pathway
Summary
Phenolic glycolipids (PGLs) are polyketide synthase products that are only synthesized by a subset of pathogenic mycobacteria, including the W-Beijing family of Mycobacterium tuberculosis strains and Mycobacterium leprae [1,2,3]. While the association between PGL-tb and mycobacterial virulence later appeared more complex, the antiinflammatory activity of PGL-tb was confirmed, using naturally deficient M. tuberculosis strains that were genetically engineered to express PGL-tb [5]. In line with these results, synthetic analogs of PGL-tb and M. leprae PGL-1 inhibited toll-like receptor (TLR)2-driven production of inflammatory cytokines and nitric oxide (NO) by macrophages [2, 6, 7]. Since PGL-1 bound to immobilized TLR2 in solid-phase assays, it was proposed that PGL-1 and PGL-tb can act as TLR2 antagonists [2]
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