Lipid droplet formation in Mycobacterium tuberculosis infected macrophages requires IFN-γ/HIF-1α signaling and supports host defense

Abstract

Lipid droplet (LD) formation occurs during infection of macrophages with numerous intracellular pathogens, including Mycobacterium tuberculosis. It is believed that M. tuberculosis and other bacteria specifically provoke LD formation as a pathogenic strategy in order to create a depot of host lipids for use as a carbon source to fuel intracellular growth. Here we show that LD formation is not a bacterially driven process during M. tuberculosis infection, but rather occurs as a result of immune activation of macrophages as part of a host defense mechanism. We show that an IFN-γ driven, HIF-1α dependent signaling pathway, previously implicated in host defense, redistributes macrophage lipids into LDs. Furthermore, we show that M. tuberculosis is able to acquire host lipids in the absence of LDs, but not in the presence of IFN-γ induced LDs. This result uncouples macrophage LD formation from bacterial acquisition of host lipids. In addition, we show that IFN-γ driven LD formation supports the production of host protective eicosanoids including PGE2 and LXB4. Finally, we demonstrate that HIF-1α and its target gene Hig2 are required for the majority of LD formation in the lungs of mice infected with M. tuberculosis, thus demonstrating that immune activation provides the primary stimulus for LD formation in vivo. Taken together our data demonstrate that macrophage LD formation is a host-driven component of the adaptive immune response to M. tuberculosis, and suggest that macrophage LDs are not an important source of nutrients for M. tuberculosis.

Activating transcription factor 3 modulates the macrophage immune response toMycobacterium tuberculosisinfection via reciprocal regulation of inflammatory genes and lipid body formation

“…It is likely that the differences between our observations and those ofKnight et al (2018) are due to differences in the two strains used, in the MOI chosen and in the time of infection. Interestingly, we demonstrate that ATF3 interacts with BRG1 in M.tuberculosis-infected macrophages.…”

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…However, the presence of IFN‐γ is not sufficient to induce LDs accumulation, requiring a second signal via TLR2, which does not exclude the M. tuberculosis as a possible inducer of LDs biogenesis. Interestingly, in this system, M. tuberculosis was able to acquire host lipids in the absence of LDs but not in the presence of IFN‐γ‐induced LDs . Although it seems contradictory to current literature, the induction of LDs as a host response cannot be underestimated, which suggests that LD is an initial protective organelle to the host but some pathogens may have co‐opted it over pathogen‐host co‐evolution.…”

“…In this context, it has been experimentally demonstrated that LDs are main sites of production of leukotriene C 4 (LTC 4 ), leukotriene B 4 (LTB 4 ), prostaglandin E 2 (PGE 2 ), prostaglandin D 2 (PGD 2 ), and eoxin C 4 (EXC 4 ) during inflammatory and infectious conditions. Other data further indicate that LDs could be the site of synthesis of lipoxin B 4 (LXB 4 ) and prostaglandin F2alpha (PGF2α), however, they still need validation. Several studies have shown that numerous pathogens stimulate the biosynthesis of PGE 2 , which could act as an anti‐inflammatory mediator favoring the persistence of the pathogen .…”

“…On the other hand, Knight et al proposed that LD formation in macrophages might not be an M. tuberculosis ‐induced process but could be a glycolytic programming event dependent on IFN‐γ and HIF1‐α signaling in murine macrophages. Additionally, in this same work, IFN‐γ‐induced LDs were an important platform for the production of a broad range of host protective eicosanoids, especially LXB 4 and PGE 2 , improving the macrophage immune response . However, the presence of IFN‐γ is not sufficient to induce LDs accumulation, requiring a second signal via TLR2, which does not exclude the M. tuberculosis as a possible inducer of LDs biogenesis.…”

“…53 Downstream pathways involved in LD biogenesis were shown to involve the activation of transcription factors including master regulators of lipid metabolism and nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), liver X receptor (LXR), SREBPs, and HIF. 42,45,48,51,[54][55][56][57][58][59] Members of subfamily of PPARs, LXR, and SREBPs sense the intracellular lipid environment and modulate expression of key genes in fatty acid uptake, lipid synthesis, lipolytic enzymes, and LD biogenesis. 54,60 Of note, NF B was shown to counter-regulate LD biogenesis because its inhibition lead to enhanced TLR2-triggered LD formation.…”