29 2 Macrophage Metabolic Reprogramming in Diabetes known as CCL2), as well as reactive oxygen species (ROS). Further studies showed that ROS, together with the increased adipocytes size, will induce endoplasmic reticulum stress, leading to a pro-inflammatory and insulin-resistant phenotype in adipocytes (23). The pro-inflammatory mediators were found to induce recruitment of circulating monocytes and accumulation of adipose tissue macrophages (24). Macrophages can respond in many different ways to stimuli from their microenvironment. In the past, this was described as macrophage activation, but since the discovery of the many different types of responses of macrophages, this is also called macrophage polarization (25). Polarized macrophages were broadly classified into two main groups, i.e. classically activated (or M1) macrophages and alternatively activated (or M2) macrophages, similar to the T helper 1/T helper 2 (Th1/Th2) dichotomy of helper T lymphocytes (26). However, it is now recognized that this view is too simplistic and that polarization states are better described as a continuous spectrum of responses (27). Macrophage responses are currently mostly described by a combination of expression of extracellular and intracellular markers, including production of specific cytokines. The most widely studied and longest known activation response, i.e. classical activation, is induced by pro-inflammatory stimuli generated by infections with micro-organisms (25). These classically activated macrophages (often still called M1 macrophages) possess high antigen-presenting capacity and high potency to produce pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), IL-1β, and IL-23, as well as toxic mediators, such as ROS and nitric oxide (NO) (28). This type of response induces and supports Th1 responses (29). Phenotypically, classically activated macrophages express high levels of major histocompatibility complex class II (MHC II) proteins, and costimulatory molecules CD80 and CD86 in humans (7,30), as shown in Figure 2.
RkJQdWJsaXNoZXIy MTk4NDMw