Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function.
CD40, a costimulatory molecule expressed on macrophages, induces expression of interleukin 12 (IL-12) in uninfected macrophages and IL-10 in macrophages infected with Leishmania major. IL-12 suppresses, whereas IL-10 enhances, L. major infection. The mechanisms that regulate this difference in CD40-induced cytokine production remain unclear, but it is known that L. major depletes cholesterol. Here we show that cholesterol influenced the assembly of distinct CD40 signalosomes. Depletion of membrane cholesterol inhibited the assembly of an IL-12-inducing CD40 signalosome containing the adaptors TRAF2, TRAF3 and TRAF5 and the kinase Lyn and promoted the assembly of an IL-10-inducing CD40 signalosome containing the adaptor TRAF6 and the kinase Syk. Thus, cholesterol depletion might represent an immune-evasion strategy used by L. major.
Rub
Abdur
A
National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
Dey
Ranadhir
R
Jadhav
Meenakshi
M
Kamat
Rohan
R
Chakkaramakkil
Santhosh
S
Majumdar
Subrata
S
Mukhopadhyaya
Robin
R
Saha
Bhaskar
B
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism*; D018320:Leishmania major / Q000276:immunology* / Q000378:metabolism; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000276:immunology / Q000378:metabolism
D019013:CD40 Antigens; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D002784:Cholesterol