Figure 4. Obese white adipose tissue (WAT) is characterized by type 1 cytokine-associated immune responses.
In obese WAT, adipocyte hypertrophy is associated with hypoxia and adipocyte cell death. Dead and neighboring adipocytes produce pro-inflammatory signals such as Monocyte chemotractant protein 1 (MCP1), C-X-C motif chemokine 12 (CXCL12), Retinol binding protein 4 (RBP4) and Resistin that are associated with the recruitment of classically activated macrophages (MP) into WAT and MP activation. MP accumulation in WAT is also mediated by pro-inflammatory invariant natural killer T (iNKT) cells that exhibit impaired production of interleukin (IL)-10 and upregulated production of Tumor necrosis factor-α (TNF-α), and by CD8+ cytotoxic T cells that produce Interferon (IFN)-γ. These factors also promote MP activation and upregulate Major histocompatibility complex class II (MHC II) on MP and adipocytes. MHC II-mediated antigen presentation by MP and adipocytes stimulates polarization of CD4+ T cells towards a T helper type 1 (Th1) phenotype. Supporting this process are TNF-α, IFN-γ, IL-1β and IL-6 produced by MP cells, dysregulated alternatively activated macrophages (AAMacs), iNKT cells and CD8+ T cells. In addition, leptin is upregulated in obese WAT, and this factor also promotes Th1 cell polarization. MP cells, CD8+ T cells and Th1 cells collectively interact to form crown-like structures (CLS) to facilitate phagocytosis of dead adipocytes. This process further promotes antigen presentation and type 1 immune responses, establishing a vicious cycle. Type 1 cytokines such as TNF-α and IFN-γ act directly on adipocytes to impair insulin action, leading to insulin resistance. Dysregulated AAMacs also produce type 1 cytokines in the setting of obesity to contribute to insulin resistance. AAMacs also lose their capacity to store iron, resulting in redistribution of iron to adipocytes. This results in iron-initiated lipid peroxidation that causes reactive oxygen species (ROS) production, insulin resistance and mitochondrial dysfunction. In addition, AAMacs in obese WAT promote collagen deposition in WAT and fibrosis, leading ultimately to exacerbated hypoxia and inflammation and potentiation of the type 1 immune response. These processes occur in the setting of decreased abundance of regulatory T cell (Treg), Group 2 innate lymphoid cell (ILC2) and eosinophils (Eos) that promote insulin sensitivity and metabolic homeostasis in WAT in the steady state.