Mycobacterial phosphatidylinositol mannosides negatively regulate host Toll-like receptor 4, MyD88-dependent proinflammatory cytokines, and TRIF-dependent co-stimulatory molecule expression.
Mycobacterium tuberculosis modulates host immune responses through proteins and complex glycolipids. Here, we report that the glycosylphosphatidylinositol anchor phosphatidyl-myo-inositol hexamannosides PIM(6) or PIM(2) exert potent anti-inflammatory activities. PIM strongly inhibited the Toll-like receptor (TLR4) and myeloid differentiation protein 88 (MyD88)-mediated release of NO, cytokines, and chemokines, including tumor necrosis factor (TNF), interleukin 12 (IL-12) p40, IL-6, keratinocyte-derived chemokine, and also IL-10 by lipopolysaccharide (LPS)-activated macrophages. This effect was independent of the presence of TLR2. PIM also reduced the LPS-induced MyD88-independent, TIR domain-containing adaptor protein inducing interferon beta (TRIF)-mediated expression of co-stimulatory receptors. PIM inhibited LPS/TLR4-induced NFkappaB translocation. Synthetic PIM(1) and a PIM(2) mimetic recapitulated these in vitro activities and inhibited endotoxin-induced airway inflammation, TNF and keratinocyte-derived chemokine secretion, and neutrophil recruitment in vivo. Mannosyl, two acyl chains, and phosphatidyl residues are essential for PIM anti-inflammatory activity, whereas the inosityl moiety is dispensable. Therefore, PIM exert potent antiinflammatory effects both in vitro and in vivo that may contribute to the strategy developed by mycobacteria for repressing the host innate immunity, and synthetic PIM analogs represent powerful anti-inflammatory leads.
Doz
Emilie
E
Orleans University and CNRS, Molecular Immunology and Embryology, UMR6218, France.
Rose
Stéphanie
S
Court
Nathalie
N
Front
Sophie
S
Vasseur
Virginie
V
Charron
Sabine
S
Gilleron
Martine
M
Puzo
Germain
G
Fremaux
Isabelle
I
Delneste
Yves
Y
Erard
François
F
Ryffel
Bernhard
B
Martin
Olivier R
OR
Quesniaux
Valerie F J
VF
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D010716:Phosphatidylinositols / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D053594:Myeloid Differentiation Factor 88; D010716:Phosphatidylinositols; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C034154:phosphatidylinositol mannoside