Macrophages are vital cells in the body's innate immune response. By inhabiting almost all tissues in the body, these cells have a key role in maintaining the healthy state of organs while constantly removing dying cells and eliminating microbes that invade the tissues.
As cells specialized for devouring and eating, macrophages are well adapted to take up, digest, and inevitably destroy foreign materials in the body. On the other hand, some microorganisms, such as Salmonella, have developed strategies to evade the macrophages' digestion attempts, leading to severe Typhoid infections and inflammations.
Analyzing Digestion Cell Organelle and Signaling
Researchers from the MPI of Immunobiology and Epigenetics, Freiburg, reported in their latest study published in the journal Nature Metabolism, titled "TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages," how inter-organellar crosstalk between lysosomes and mitochondria restricts the growth of bacteria, like Salmonella, inside macrophages.
Like most cells, the interior of macrophages is subdivided into distinct compartments, and organelles, each taking over specific functions inside the cell. Since macrophages are scavenger cells, they have a prominent digestion organelle, the phago-lysosome, where devoured microorganisms are degraded into pieces and are inactivated.
Angelika Rambold, the study's lead author, says that it has long been known that the Transcription Factor EB (TFEB) molecule is vital for regulating the phago-lysosomal system. Recent evidence suggests that the molecule also supports the defense of the cells against bacteria, reports ScienceDaily.
Together with her team, Rambold wanted to understand how the TFEB molecule mediates anti-bacterial roles in macrophages. The team confirmed earlier findings suggesting that a broad range of microbes, inflammatory stimuli, and bacteria activated TFEB and the phago-lysosomal system.
She explains that it was logical that pathogen signals triggered the molecule as macrophages needed more active digestion systems faster as they devoured bacteria. However, interestingly, experiments also revealed strong effects of TFEB activation on mitochondria. This was unexpected and novel to the team.
Mitochondria Instruction Increases Macrophages' Anti-Microbial Activity
Mitochondria are a well-known cellular organelle. These are composed of inner and outer membranes and are a primary site for cellular respiration and the release of nutrients and energy. Additionally, mitochondria in immune cells were only recently identified as sources of anti-microbial metabolites.
By using broad experiment tools, including molecular biology, metabolomics, and imaging techniques, researchers at Max Planck identified the pathway controlling the unexpected crosstalk between mitochondria and lysosomes.
Rambold explains that macrophages use extensive inter-organellar communication: where the lysosome activates the TFEb molecule, shuttling into the nucleus where it controls the transcript of the IRG1 protein. The protein is imported into the mitochondria, acting as a major enzyme to produce antimicrobial metabolites.
In the midst of the increasing emergence of multidrug-resistant bacteria, with more than 10 million deaths annually by 2050, it is vital to identify new strategies to control bacterial infections in the body that escape innate immune mechanisms.
Utilizing the pathway of TFEB-IRG1-Itaconic to treat infections caused by bacteria may promote a promising path to treatment.
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