The immune response in the brain, particularly the role of microglia, has been extensively studied. Microglia, the brain-specific tissue macrophages, play a crucial role in repairing and resolving tissue injury and restoring normal homeostasis. This review examines the mechanisms that lead to the reduction of self-toxicity and the repair and restructuring of the damaged extracellular matrix in the brain. Two complementary functional macrophage states, alternative activation and acquired deactivation, are identified. Alternative activation is induced by anti-inflammatory cytokines such as IL-4, IL-13, IL-10, and TGF-β, leading to a shift from a proinflammatory to an anti-inflammatory state. This state is characterized by reduced expression of proinflammatory cytokines and increased production of repair-related genes. Acquired deactivation, on the other hand, is induced by exposure to apoptotic cells or by TGF-β and IL-10, resulting in a strong immunosuppressive state. The review also discusses the role of lectins, arginase-NOS2 balance, and extracellular matrix components in alternative activation, as well as the mechanisms underlying acquired deactivation. The implications of these findings for chronic neuroinflammation and Alzheimer's disease are also explored.The immune response in the brain, particularly the role of microglia, has been extensively studied. Microglia, the brain-specific tissue macrophages, play a crucial role in repairing and resolving tissue injury and restoring normal homeostasis. This review examines the mechanisms that lead to the reduction of self-toxicity and the repair and restructuring of the damaged extracellular matrix in the brain. Two complementary functional macrophage states, alternative activation and acquired deactivation, are identified. Alternative activation is induced by anti-inflammatory cytokines such as IL-4, IL-13, IL-10, and TGF-β, leading to a shift from a proinflammatory to an anti-inflammatory state. This state is characterized by reduced expression of proinflammatory cytokines and increased production of repair-related genes. Acquired deactivation, on the other hand, is induced by exposure to apoptotic cells or by TGF-β and IL-10, resulting in a strong immunosuppressive state. The review also discusses the role of lectins, arginase-NOS2 balance, and extracellular matrix components in alternative activation, as well as the mechanisms underlying acquired deactivation. The implications of these findings for chronic neuroinflammation and Alzheimer's disease are also explored.