9 1 General Introduction at reducing inflammation, slowing disease progression, and improving the quality of life for individuals living with this chronic respiratory condition. T2DM is characterized by chronic low-grade inflammation in various tissues involved in energy regulation, including fat, liver, and pancreatic islets (6). This inflammation is marked by increased levels of pro-inflammatory cytokines and non-esterified free fatty acids (FFA), which contribute to insulin resistance and beta-cell dysfunction. In T2DM, pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, and IL-1α are produced in higher quantities, contributing to obesity-related inflammation and impairing insulin signaling (7). These cytokines also contribute to the development of microvascular complications associated with diabetes, including retinopathy, polyneuropathy, and nephropathy (8). The inflammatory effects of obesity were defined for the first time in 1993 when it was shown that adipose tissue from obese individuals expressed elevated levels of TNF-α, a proinflammatory cytokine, primarily secreted by macrophages (9). MACROPHAGES Macrophages are cells of the innate immune system derived from hematopoietic stem cells (HSCs) of the bone marrow or from erythro-myeloid progenitors (EMPs) of the fetal yolk sac (10). HSCs differentiate in myeloid (MPs) and lymphoid (LPs) committed precursors. MPs will then differentiate into monocytes, macrophages, and dendritic cell precursors (MDP). Two monocyte subsets (resident, lymphocyte antigen 6c negative, Ly6C-/low, and inflammatory Ly6C+/high) are released in the circulation, and, in case of infection, Ly6C+ can migrate into local inflammatory sites and differentiate into inflammatory macrophages (11,12). Macrophage polarization Macrophages, a type of immune cell, can be polarized into different groups based on their response to the microenvironment. The three main groups are M1 (classically activated) macrophages, M2 (alternatively activated) macrophages, and M2-like (regulatory) macrophages (13). The classification is determined by specific molecular markers, chemokine receptors, and cytokine production (14). M1 macrophages are activated by inflammatory stimuli and produce pro-inflammatory cytokines, promoting a Th1 immune response (15,16). They express markers like MHC II, CD68, CD80, and CD86 (17). M2 macrophages are associated with tissue remodeling and are activated by interleukins 4 and 13 (18–20). They express CD206 and transglutaminase 2, and have limited antigen-presenting capabilities. M2-like macrophages are induced by anti-inflammatory stimuli and secrete high levels of
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