The 19？kDa Mycobacterium tuberculosis Lipoprotein (LpqH) Induces Macrophage Apoptosis through Extrinsic and Intrinsic Pathways: A Role for the Mitochondrial Apoptosis-Inducing Factor
We describe the association of caspase-dependent and caspase-independent mechanisms in macrophage apoptosis induced by LpqH, a 19？kDa Mycobacterium tuberculosis lipoprotein. LpqH triggered TLR2 activation, with upregulation of death receptors and ligands, which was followed by a death receptor signaling cascade with activation of initiator caspase 8 and executioner caspase 3. In this caspase-mediated phase, mitochondrial factors were involved in loss of mitochondrial transmembrane potential ( ), release of cytochrome c, and caspase 9 activation. Interestingly, a caspase-independent pathway was also identified; by immunoblot, the mitochondrial apoptosis inducing factor (AIF) was demonstrated in nuclei and cytosol of LpqH-treated macrophages. Confocal microscopy revealed translocation of AIF to the nuclei of the majority of apoptotic cells. These findings emphasize the complex and redundant nature of the macrophage death response to mycobacteria. 1. Introduction Macrophage (MO) apoptosis during Mycobacterium tuberculosis (Mtb) infection has focused much attention on its possible role in disease pathogenesis. A number of findings support this view; it has been shown that virulent mycobacterial strains are less apoptogenic than their attenuated counterparts [1] and MO proapoptotic genes are downregulated by virulent strains while the opposite occurs with avirulent mycobacteria [2]. In contrast with latent infection, in active TB patients the expression of genes that promote apoptosis is diminished [3]. These data and the identification of genes that inhibit MO apoptosis in some Mtb mutants [4] have added further support to the view that the ability of Mtb to prevent the apoptotic death of host cells is a virulence trait aimed to preserve its cellular niche. On the other hand, that MO apoptosis represents an innate immune response of the host is suggested by decreased viability of bacilli in apoptotic MO [5–7]. There is also evidence that dendritic cells that have ingested apoptotic MO infected by Mtb can activate T cells through a process known as cross-priming which results in the activation of CD8+ T cells [7, 8]. It is also of interest the identification of Mtb proapoptotic mutants that induce higher T cell immunity which favors the control of infection [9]. Knowledge about the mechanisms involved in the death of mycobacteria-infected MOs has greatly increased during the last decade. Initially, it was characterized as extrinsic type, caspase-dependent apoptosis with TNF-α activation [10, 11]. More recent studies have come to show that MO apoptosis in
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