Adipose Tissue Immunometabolism and Apoptotic Cell Clearance

Abstract

The safe removal of apoptotic debris by macrophages—often referred to as efferocytosis—is crucial for maintaining tissue integrity and preventing self-immunity or tissue damaging inflammation. Macrophages clear tissues of hazardous materials from dying cells and ultimately adopt a pro-resolving activation state. However, adipocyte apoptosis is an inflammation-generating process, and the removal of apoptotic adipocytes by so-called adipose tissue macrophages triggers a sequence of events that lead to meta-inflammation and obesity-associated metabolic diseases. Signals that allow apoptotic cells to control macrophage immune functions are complex and involve metabolites released by the apoptotic cells and also metabolites produced by the macrophages during the digestion of apoptotic cell contents. This review provides a concise summary of the adipocyte-derived metabolites that potentially control adipose tissue macrophage immune functions and, hence, may induce or alleviate adipose tissue inflammation.

Effects of Probiotic Supplementation during Pregnancy on the Future Maternal Risk of Metabolic Syndrome

“…Currently, adipose tissue is considered as a potent immune and endocrine organ [ 94 ]. It consists of endothelial cells, preadipocytes, adipocytes, fibroblasts, and immune cells, including mainly T cells, B cells, macrophages, and neutrophils [ 95 , 96 , 97 ]. Excessive caloric intake, body weight and diet control the cellular composition of adipose tissue, especially the composition of the immune cells.…”

The regulation of efferocytosis signaling pathways and adipose tissue homeostasis in physiological conditions and obesity: Current understanding and treatment options

“…ACs also contain various metabolites, such as cell membranes and cytosolic metabolites, such as ATP, UTP, polyamines, lactate, and creatine, nucleic acids, fat‐soluble vitamins, lipid metabolites, and mitochondrial membranes. These metabolites may act as “Find‐Me” signals, impacting macrophage functions (reviewed in Röszer 66 ).…”

“…Administration of lactate causes adipose browning, providing protection against HFDinduced obesity in mice. 169 Efferocytosis promotes lactate secretion in macrophages, 66,159 the released lactate promoting an antiinflammatory state. 151 SLC2A1 localization facilitates glucose transport to macrophages.…”

Metabolic impact of adipose tissue macrophages in the early postnatal life

“…Similarly, further breast milk‐derived lipids, such as the 12,13‐dihydroxy‐9Z‐octadecenoic acid have the potential to control early adipocyte development, albeit the underlying mechanisms are still to be understood 122 . Further metabolites—other than lipids—may induce ATM activation, as reviewed before 20 . For instance, hyperglycemia sustains a proinflammatory macrophage activation, 123 increases sensitivity of macrophages to proinflammatory signals, and reduces their phagocytic capacity 124 .…”

“…ATMs engulf lipid overloaded and apoptotic fat cells, by forming multinucleated syncytia, so‐called crown‐like structures around the dying fat cells 1–7,16,18,19 . Albeit apoptotic cell uptake promotes anti‐inflammatory macrophage activation in most tissues, removal of apoptotic adipocytes triggers a proinflammatory ATM activation 20 . Since ATMs are situated within a complex adipose tissue immune cell niche, built up by mast cells, T cells, and B cells, a proinflammatory ATM activation may initiate a cascade of intercellular signaling events, leading to an uncontrolled inflammation (Figure 1).…”