01969nas a2200313   4500000000100000008004100001653001200042653000900054653000900063653000900072653001600081653001700097653002500114100001600139700001200155700001300167700001300180700002300193700001400216700001200230700001300242700001500255245010500270856007000375300000600445490000600451520118400457022001401641       2018                            d10aleprosy10aTLR410aTRIF10aiNOS10aMacrophages10aMycobacteria10aPhenolic glycolipids1 aOldenburg R1 aMayau V1 aPrandi J1 aArbues A1 aAstarie-Dequeker C1 aGuilhot C1 aWerts C1 aWinter N1 aDemangel C00aMycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages.  uhttps://www.frontiersin.org/articles/10.3389/fimmu.2018.00002/pdf  a20 v93 a<p>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.</p>
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