Extracellular vesicles in obesity and its associated inflammation

Abstract

Obesity is characterized by low-grade, chronic inflammation, which promotes insulin resistance and diabetes. Obesity can lead to the development and progression of many autoimmune diseases, including inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, thyroid autoimmunity, and type 1 diabetes mellitus (T1DM). These diseases result from an alteration of self-tolerance by promoting pro-inflammatory immune response by lowering numbers of regulatory T cells (T_regs), increasing Th1 and Th17 immune responses, and inflammatory cytokine production. Therefore, understanding the immunological changes that lead to this low-grade inflammatory milieu becomes crucial for the development of therapies that suppress the risk of autoimmune diseases and other immunological conditions. Cells generate extracellular vesicles (EVs) to eliminate cellular waste as well as communicating the adjacent and distant cells through exchanging the components (genetic material [DNA or RNA], lipids, and proteins) between them. Immune cells and adipocytes from individuals with obesity and a high basal metabolic index (BMI) produce also release exosomes (EXOs) and microvesicles (MVs), which are collectively called EVs. These EVs play a crucial role in the development of autoimmune diseases. The current review discusses the immunological dysregulation that leads to inflammation, inflammatory diseases associated with obesity, and the role played by EXOs and MVs in the induction and progression of this devastating conditi8on.

Figure 1.. Obesity predisposes people to different diseases associated with dysregulated immune responses.

For example, different cancers, including breast cancer, T2DM, different autoimmune diseases (RA and SLE), along with increasing the susceptibility to different infections.

Figure 2.. Different physiological or pathological conditions are responsible for generating extracellular vesicles (EVs).

For example, inflammation, cell death (autophagy and apoptosis), coagulation, cancer microenvironment, and angiogenesis generate different EVs.

Figure 3.. ATs of adult obese and lean human exert different immune response due to different immune cell populations and endocrine functions.

ATs of obese people have an increased number of M1 macrophages creating a pro-inflammatory microenvironment. The adipocytes of AT secrete EVs with different adipokines responsible for immune dysregulation responsible for T2DM. On the other hand, AT of lean persons have an increased number of M2 macrophages and their adipocytes release EVs with adipokines responsible for maintaining the immune homeostasis.

Figure 4.. Different EVs in obesity the potential to modulate the immune response to predispose to different inflammatory diseases.

The hepatocyte-derived EVs with ASPGR-1 in obese people may predispose them to autoimmune hepatitis. The high number of EXos with MIF increases the MIF in the circulation, which increases neutrophil life span and number, and MIF also dysregulates macrophage function through ERK1/ERK2 signaling to increase the IR and predisposes the host to T2DM. Adipocyte release EVs with PLIN1 and the Abs against PLIN1 may play role in AGL pathogenesis.

Fig. 5.. Macrophages and platelet-derived EVs in obesity and their impact on inflammation and immune-associated diseases.

The platelet-derived EVs (pEVs) may increase the susceptibility of obese people to different coagulation-associated diseases along with autoimmunity. The EVs released from macrophages of obese people with miR-146A and lncRNA GAS5 cause endothelial damage and decrease the naïve macrophage migration. On the other hand, EVs with miR-29 miR-215 increase the susceptibility to T2DM through inhibiting pancreatic β cell activity.