Abstract
Inhalation of crystalline silica (CS) particles increases the risk of pulmonary tuberculosis; however, the precise mechanism through which CS exposure facilitates Mycobacterium tuberculosis (Mtb) infection is unclear. We speculate that macrophage exposure to CS deregulates the cell death pathways that could explain, at least in part, the association observed between exposure to CS and pulmonary tuberculosis. We therefore established an in vitro model in which macrophages were exposed to CS and then infected with Mtb. Expression of surface markers was analyzed by flow cytometry, JNK1/2, ASK1, caspase 9, P-p38, Bcl-2 and Mcl-1 were analyzed by Western blot, and cytokines by ELISA. Our results show that exposure to CS limits macrophage ability to control Mtb growth. Moreover, this exposure reduced the expression of TLR2, Bcl-2 and Mcl-1, but increased that of JNK1 and ASK1 molecules in the macrophages. Finally, when the pre-exposed macrophages were infected with Mtb, the concentrations of TNFα, IL-1β and caspase-9 expression increased. This pro-inflammatory profile of the macrophage unbalanced the apoptosis/necrosis pathway. Taken together, these data suggest that macrophages exposed to CS are sensitized to cell death by MAPK kinase-dependent signaling pathway. Secretion of TNF-α and IL-1β by Mtb-infected macrophages promotes necrosis, and this deregulation of cell death pathways may favor the release of viable bacilli, thus leading to the progression of tuberculosis.
Highlights
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb)
In vitro treatment with crystalline silica (CS) decreased in a dose-dependent manner the capacity of the macrophages to control the intracellular bacterial replication of Mtb in both THP-1 and monocyte-derived macrophages (MDMs) macrophages (Figures 1A and B)
Exposure to CS for 24 h did not modify the expression of CD68, CD80, CD86, HLA-DR or MMR; when unexposed THP-1 macrophages were infected with Mtb, the frequency and mean fluorescence intensity (MFI) changed, suggesting that under these experimental conditions CS was not responsible for the observed phenotypic changes
Summary
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), in 2011 there were an estimated 8.7 million incident cases of tuberculosis and 1.4 million people died of this disease [1,2]. Alveolar macrophages (AM) are critical components of the innate and adaptive immune systems, and the prototypical host cell for diverse pathogens, including Mtb and many airborne particles [6,7]. Macrophages and alveolar type II cells exposed to CS increase cellular stress, the secretion of reactive oxygen species (ROS) and pro-inflammatory cytokines, such as IL-1β, by cells undergoing apoptosis [11,12,13,14,15]. Active secretion of IL-1β that is partially dependent on caspase-1 activity, which in turn requires the assembly and activation of the Nalp inflammasome, is a new, innate immune mechanism that contributes to mycobacterial clearance by promoting phagolysosomal maturation and pyroptosis of Mtb-infected macrophages [19,20,21]
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