Sirt1 activation negatively regulates overt apoptosis in Mtb-infected macrophage through Bax

Highlights

• Sirt1 activation inhibits Mtb-induced overt apoptosis through Bax.

• Sirt1 activation inhibits M. tuberculosis growth.

• Sirt1 expression is decreased in Mtb-infected macrophages.

Abstract

Apoptotic pathways play an important role in Mycobacterium tuberculosis-infected macrophages. Sirt1 is a member of the deacetylase family that is known to promote apoptosis resistance in many mammalian cells. However, the apoptotic role of Sirt1 in the process of M. tuberculosis infection remains unclear. With the help of mouse macrophage samples, 129/Sv background mice, and PBMCs-derived macrophages from healthy controls and patients with tuberculosis, we have shown that M. tuberculosis infection reduced Sirt1 mRNA and protein expression, however, increased Bax mRNA and protein expression. Further, we found that resveratrol, a Sirt1 activator, inhibited M. tuberculosis-induced Bax expression. Thus, it seems that Sirt1 acts as a novel regulator of apoptosis signaling in M. tuberculosis infection via its effects on Bax. Sirt1 activation may therefore be a new candidate for the prevention and treatment of tuberculosis.

Introduction

Tuberculosis is the ninth leading cause of death worldwide with a higher ranking than HIV/AIDS [1]. Macrophages death is one of the essential responses to tuberculosis development. Secreted lipoproteins (19 kD and 38 kD) of mycobacteria are detected by Toll-like receptor 2, which mediates endocytosis by macrophages, activating apoptosis and inflammatory reactions [2], [3], [4], [5]. Although activation of TLR-induced apoptosis is important for host innate defense response that clears M. tuberculosis, overt activation of the apoptosis may lead to tissue damage and TB progression [6]. Apoptotic pathway proteins may play an important role in host immune reactions against M. tuberculosis infection, and it would be interesting to explore them as targets in immunotherapy against M. tuberculosis.

The Sirt1 (silent information regulator proteins), a NAD-dependent deacetylase, is mainly localized in the nucleus, but it is also present in the cytosol when needed [7]. Sirt1 has been reported to inhibit apoptosis and inflammatory responses in many mammalian cells [8], [9]. Some studies provide a link between Sirt1 activation and tuberculosis pathogenesis through inflammatory responses [10], [11]. But it remains no clear between Sirt1 activation and tuberculosis pathogenesis through apoptotic responses.

Bax (B-cell lymphoma 2-associated X protein), a member of the Bcl-2 family, is a pro-apoptotic factor [12]. Most reports show that Bax brings about its effect through the p53-Bax axis [13], [14]. Sirt1 interacts with p53, directly de-acetylates it, and thereby influences p53-mediated apoptosis [9], [15]. Bmf (Bcl-2-modifying factor), another member of the Bcl-2 family, is also a pro-apoptotic factor. Recently, it was reported that the nuclear body protein Sp110 upregulated Bmf by inhibiting miR-125a, inducing macrophage apoptosis following M. tuberculosis infection [16]. During M. tuberculosis infection, it is unclear whether Sirt1 regulates the expression of Bax and Bmf to mediate apoptosis responses. It would be interesting to explore the interactions of Sirt1 with all these apoptosis-related proteins in M. tuberculosis infection to understand how these proteins may be used in immunotherapy.

Resveratrol (a naturally occurring polyphenolic compound) is an activator of Sirt1 that is implicated in the regulation of numerous cellular responses such as cell cycle arrest, differentiation, and apoptosis in various cancer cell lines. Based on all the above information, the present study was carried out to investigate whether Sirt1 plays a role in M. tuberculosis-induced macrophage apoptosis, and also to elucidate the involved proteins and pathways.