Sirtuin 3 Downregulation in -Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death.

induces metabolic reprogramming in macrophages like the Warburg effect. This enhances antimicrobial performance at the expense of increased inflammation, which may promote a pathogen-permissive host environment. Since the NAD-dependent protein deacetylase Sirtuin 3 (SIRT3) is an important regulator of mitochondrial metabolism and cellular redox homeostasis, we hypothesized that SIRT3 modulation mediates -induced metabolic reprogramming.

Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Infection.

is an extremely successful pathogen, and its success is widely attributed to its ability to manipulate the intracellular environment of macrophages. A central phenomenon of tuberculosis pathology enabling immune evasion is the capacity of virulent (H37Rv) to induce macrophage necrosis, which facilitates the escape of the mycobacteria from the macrophage and spread of infection. In contrast, avirulent (H37Ra) induces macrophage apoptosis, which permits Ag presentation and activation of adaptive immunity.

Bcl-x mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages.

Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host Mϕ, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected Mϕ is dependent on the action of the cytosolic Receptor Interacting Protein Kinase 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphoma-extra large (Bcl-x). RIPK3-deficient Mϕ are able to better control bacterial growth in vitro and in vivo.

The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis.

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mϕs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE2 receptor EP2. However, human Mϕs also express EP4, a PGE2 receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mϕs have been unclear.

IL-1β promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation.

In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effector Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3.