Critical role of methylglyoxal and AGE in mycobacteria-induced macrophage apoptosis and activation.
Apoptosis and activation of macrophages play an important role in the host response to mycobacterial infection involving TNF-alpha as a critical autocrine mediator. The underlying mechanisms are still ill-defined. Here, we demonstrate elevated levels of methylglyoxal (MG), a small and reactive molecule that is usually a physiological product of various metabolic pathways, and advanced glycation end products (AGE) during mycobacterial infection of macrophages, leading to apoptosis and activation of macrophages. Moreover, we demonstrate abundant AGE in pulmonary lesions of tuberculosis (TB) patients. Global gene expression profiling of MG-treated macrophages revealed a diverse spectrum of functions induced by MG, including apoptosis and immune response. Our results not only provide first evidence for the involvement of MG and AGE in TB, but also form a basis for novel intervention strategies against infectious diseases in which MG and AGE play critical roles.
Rachman
Helmy
H
Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.
Kim
Nayoung
N
Ulrichs
Timo
T
Baumann
Sven
S
Pradl
Lydia
L
Nasser Eddine
Ali
A
Bild
Matthias
M
Rother
Marion
M
Kuban
Ralf-Jürgen
RJ
Lee
Jong Seok
JS
Hurwitz
Robert
R
Brinkmann
Volker
V
Kosmiadi
George A
GA
Kaufmann
Stefan H E
SH
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008262:Macrophage Activation / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D009161:Mycobacterium / Q000472:pathogenicity*; D009164:Mycobacterium Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009163:Mycobacterium bovis / Q000472:pathogenicity; D011765:Pyruvaldehyde / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D017127:Glycation End Products, Advanced; D014409:Tumor Necrosis Factor-alpha; D011765:Pyruvaldehyde