Opposing roles of PGE2 and LXA4 in the regulation of necrosis of Mycobacterium tuberculosis infected macrophages (B175)

• Published in: The Journal of immunology (1950) 2007-04, Vol.178 (1_Supplement), p.LB37-LB37
• Main Authors: Chen, Minjian, Remold, Heinz G.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.178.Supp.B175

The innate immune response against attenuated Mycobacterium tuberculosis (Mtb) can include induction of apoptosis of the host macrophage (Mφ) that limits intracellular growth by sequestering bacilli in apoptotic bodies, facilitates efficient pathogen removal and enhances antigen presentation. In infection with virulent H37Rv a completely different mechanism, necrosis, dominates the outcome of cell death. Necrosis serves as a microbial virulence mechanism allowing dissemination of the pathogen. Initiation of necrosis depends on the induction of mitochondrial inner membrane perturbation causing significant mitochondrial transmembrane potential (Δψm) loss. Here we report that attenuated H37Ra induces in Mφ the production of the prostanoids PGE2, PGD2, PGF2α, and TXA2. PGE2 suppresses Δψm loss in H37Rv-infeted Mφ and rescues the infected Mφ from necrosis. In contrast, virulent H37Rv induces the production of LXA4, which triggers Mφ necrosis by blocking prostanoid synthesis leading to Δψm loss. The production of the above mentioned prostanoids is not induced in H37Rv-infected Mφ. PGE2 acts through the engagement of the PGE2 receptor EP-2, which induces cAMP leading to PI3K and PKA activation. Thus, eicosanoids play a crucial role in the regulation of necrosis of Mtb-infected Mφ and are of critical importance in determining the outcome of an Mtb infection (Supported by NIH grant AI50216).