Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE₂ and LXA₄ in the induction of macrophage death

Journal of Experimental Microbiology. Vol. 205, No. 12, 2791-2801

Speaker: 陳怡璇                                          Time: 13:10~14:00, Mar. 25, 2009

Commentator: 劉清泉 醫師                       Place: Room 601

Abstract:

        Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. After phagocytosed by macrophages (Mφ), the virulent Mtb prevents apoptosis of Mφ, which may enhance antigen presenting to dendritic cells and facilitate efficient pathogen killing¹. However, it was lately shown that Mtb-induced Mφ necrosis may afford a protective milieu for this pathogen. It has been found previously that the virulent Mtb strain H37Rv induced Mφ necrosis by triggering the mitochondrial permeability transition (MPT)², while the avirulent Mtb strain H37Ra induced Mφ apoptosis instead, and the opposite outcomes are regulated by eicosanoids³. Lipoxin A₄ (LXA₄) and prostaglandin E₂ (PGE₂), a subtype of prostanoid, are two groups of eicosanoids. In this study, the authors further found that H37Rv triggered LXA₄ production and inhibited prostanoid production in Mφ, while H37Ra showed the opposite effects. To further investigate the role of LXA₄ and PGE₂, they infected LXA₄–pretreated Mφ with H37Ra and found that the degrees of Mφ mecrosis and decrease of PGE₂ concentration were higher compared to the non-treated Mφ. Moreover, Mφ necrosiswas significantly suppressed by adding PGE₂ in both H37Rv-infected Mφ and H37Ra-infected PGE₂-deficient Mφ. These results suggest that PGE₂ may prevent Mφ from Mtb-induced necrosis and the protective effect may be inhibited by LXA₄. The action of PGE₂ on Mφ is mediated by four G protein-coupled E prostanoid (EP) receptors⁴. The necrosis of H37Ra-infected EP2^-/- Mφ could not be inhibited even by adding large amount of PGE₂, indicating that the protective effect of PGE₂ on Mtb-infected Mφ is mediated via the EP2 receptor. In conclusion, the fate of infected Mφ is critically determined by the concentration of LXA₄ and PGE₂ produced in response to Mtb infection.

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