期刊
BMC IMMUNOLOGY
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12865-015-0080-5
关键词
Wnt/beta-catenin signaling; Alveolar macrophages; Cell death; Necrosis; Mycobacterial infection
类别
资金
- National Key Basic Research Program of China (973 Program) [2012CB518801]
- National Natural Science Foundation of China [31460301, 31472191, 31160515]
Background: Necrosis of alveolar macrophages following Mycobacterium tuberculosis infection has been demonstrated to play a vital role in the pathogenesis of tuberculosis. Our previous study demonstrated that Wnt/beta-catenin signaling was able to promote mycobacteria-infected cell apoptosis by a caspase-dependent pathway. However, the functionality of this signaling in the necrosis of macrophage following mycobacterial infection remains largely unknown. Methods: Murine macrophage RAW264.7 cells were infected with Bacillus Calmette-Guerin (BCG) in the presence of Wnt/beta-catenin signaling. The necrotic cell death was determined by cytometric assay and electronic microscopy; the productions of reactive oxygen species (ROS) and reduced glutathione (GSH) were measured by a cytometric analysis and an enzyme-linked immunosorbent assay, respectively; and the activity of poly (ADP-ribose) polymerase 1 (PARP-1)/apoptosis inhibition factor (AIF) signaling was examined by an immunoblotting assay. Results: The BCG can induce RAW264.7 macrophage cells necrosis in a dose- and time-dependent manner along with an accumulation of reactive oxygen species (ROS). Intriguingly, an enhancement of Wnt/beta-catenin signaling shows an ability to reduce the mycobacteria-induced macrophage necrosis. Mechanistically, the activation of Wnt/beta-catenin signaling is capable of inhibiting the necrotic cell death in BCG-infected RAW264.7 cells through a mechanism by which the Wnt signaling scavenges intracellular ROS accumulation and increases cellular GSH concentration. In addition, immunoblotting analysis further reveals that Wnt/beta-catenin signaling is capable of inhibiting the ROS-mediated cell necrosis in part through a PARP-1/AIF-dependent pathway. Conclusions: An activation of Wnt/beta-catenin signaling can inhibit BCG-induced macrophage necrosis by increasing the production of GSH and scavenging ROS in part through a mechanism of repression of PARP-1/AIF signaling pathway. This finding may thus provide an insight into the underlying mechanism of alveolar macrophage cell death in response to mycobacterial infection.
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