Immunity: Oxidative phosphorylation maintains tissue macrophage homeostasis

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Immunity: Oxidative phosphorylation maintains tissue macrophage homeostasis

Macrophages are usually derived from embryonic precursor cells or monocytes, and are distributed in major organs throughout the body.

These tissue macrophages (Those macrophages in tissues, referred to as TMFs ) are not only the main components of the innate immune response, but also participate in the maintenance of local and systemic homeostasis in complex environments.

For example, alveolar macrophages (alveolar macrophages) can remove excess surfactant, which is beneficial to lung gas exchange;

spleen red pulp macrophages (red pulp macrophages) and liver Kupffer cells are involved in red blood cell (erythrocytes) iron recycling and lipid Metabolism; while white adipose tissue macrophages are involved in lipid production and thermogenesis [1-4] .

The field of immunometabolism studies the interaction between the body’s metabolism and the function of immune cells, of course, including macrophages.

Cells can well adapt and utilize metabolites derived from sugars, amino acids, and lipids.

These nutrients perform the functions of synthesizing cellular components or supplying cellular energy through anabolic or catabolic pathways, respectively.

In eukaryotic cells, the most important energy supply pathways are glycolysis in the cytoplasm and oxidative phosphorylation in the mitochondria , followed by lactose production .

The respiration of mitochondria can use a variety of nutrients including but not limited to glucose as raw materials, and these raw materials enter the tricarboxylic acid cycle (tricarboxylic acid cycle) , undergo glutaminolysis (glutaminolysis) or fatty acid oxidation (fatty acid oxidation) , etc. 【 5] .

In vitro, bone marrow-derived macrophages (bone marrow-derived macrophages) can be induced to activate metabolic pathways under specific stimuli.

Enhanced glycolysis and abnormal tricarboxylic acid cycle can promote the evolution of macrophages into pro-inflammatory M1-like macrophages; while mitochondrial respiration of glutamine and fatty acids can promote macrophages to evolve into anti-inflammatory M2-like macrophages Cell Evolution [6-8] .

Of course, the metabolic state of these macrophages is not static. For example, large peritoneal macrophages(large peritoneal macrophages) perform microbial killing functions through glutamine-driven mitochondrial metabolism;

of course, alveolar macrophages rely on glycolysis to induce type II inflammatory responses, but do not depend on bacteria-induced inflammatory responses;

cardiac macrophages The inflammatory response of phagocytes relies on fatty acid oxidation and mitochondrial respiration.

Nevertheless, the specific metabolic state necessary to maintain the function of these macrophages under physiological conditions remains unclear.

Recently, Santiago Lamas from Centro de Biolog ́ıa Molecular “Severo Ochoa” in Madrid, Spain, and David Sancho ’s research group from Centro Nacional de Investigaciones Cardiovasculares Carlos III published an article titled Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis on Immunity , and conducted research on the above issues. in-depth research.

Immunity: Oxidative phosphorylation maintains tissue macrophage homeostasis

In vitro experiments confirmed that oxidative phosphorylation is associated with anti-inflammatory macrophages, while pro-inflammatory macrophages are dependent on glycolysis.

Of course, the specific metabolic environment required for tissue macrophages to maintain homeostasis remains largely unknown.

The author collected tissue macrophages from different organs of mice and humans and performed RNA sequencing.

Through the analysis of the sequencing results, it was found that oxidative phosphorylation is likely to be one of the main markers to distinguish different tissue macrophages.

Attenuating the level of oxidative phosphorylation by knocking out Tfam in tissue macrophages has different effects on macrophages in different tissues.

After Tfam knockout, the content of alveolar macrophages is reduced, and the ability to metabolize lipids is also reduced, which leads to increased sterol content and increased cellular stress, eventually causing cell cycle arrest in vivo.

In addition, non-infectious pathological conditions can change the tissue microenvironment, and can also affect the metabolic state and function of tissue macrophages [1,2] .

For obese people, the excessive growth of white adipose tissue caused by overnutrition will lead to an increase in cellular fat load.

The authors found that under obesity, knocking out Tfam can selectively eliminate pro-inflammatory white adipose tissue macrophages (white adipose tissue macrophages ), thereby inhibiting insulin resistance and fatty liver (hepatosteatosis) .

In conclusion, oxidative phosphorylation effectively differentiates tissue macrophages and is critical for maintaining tissue macrophage content and function in tissues subject to high levels of lipid degradation, such as proinflammatory white adipose tissue .

Immunity: Oxidative phosphorylation maintains tissue macrophage homeostasis