The immune response in the brain has been widely studied, with many studies focusing on the proinflammatory cytotoxic response of microglia, the brain's tissue macrophages. However, the brain's innate immune system shows significant heterogeneity. Microglia participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review discusses the mechanisms that lead to reduction of self-toxicity and repair of the damaged extracellular matrix in the brain. Two partially overlapping and complementary macrophage states, alternative activation and acquired deactivation, are identified. These states are involved in immunosuppressive and repair processes, and their roles in chronic neuroinflammation in the brain are discussed. The innate immune response in the brain is characterized by the primary cells being microglia, although astrocytes and neurons may also play an immune role. Microglia recognize pathogens via pattern recognition receptors, including toll-like receptors, NOD proteins, and non-TLR receptors. These receptors interact with pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to initiate cellular defense mechanisms. Downstream signaling events begin with engagement of adaptor proteins, leading to activation of transcription factors and induction of proinflammatory genes. Classical activation is reduced by inherent feedback signals that regulate specific steps in the activation process. These signals include proteins that mediate ubiquitination and degradation of TLRs, competition between functional and nonfunctional adaptor proteins, and suppressor of cytokine signaling proteins. Noncoding RNA oligonucleotides (microRNAs) also regulate gene expression by binding to 3' untranslated regions of specific target genes. Repair and resolution involve changing the macrophage activation state from a proinflammatory to a gene profile that supports repair and tissue reconstruction. This switch is induced by multiple factors, including cytoactive agents and T_H2 regulatory cells. Anti-inflammatory cytokines, such as IL-4, IL-13, IL-10, and TGF-β, are the predominant induction signals. These cytokines antagonize classical activation pathways and induce new genes and proteins involved in tissue repair and reconstruction. Alternative activation (aaMac) is characterized by the absence and presence of specific genes whose expression levels change during the switch from a proinflammatory to an anti-inflammatory state. The term alternative activation is used to describe macrophages exposed primarily to IL-4 or IL-13. Acquired deactivation is another macrophage activation state that incorporates a mixed-phenotype population that exhibits immunosuppression and is associated with uptake of apoptotic cells. Acquired deactivation is distinguished by the type of induction agents and the functional changes associated with induction. The role of macrophage functional heterogeneity in chronic inflammation of the brain, particularly in Alzheimer's disease, is discussed. The review also covers the role of lectins and alternative activation, including the mannose receptor, andThe immune response in the brain has been widely studied, with many studies focusing on the proinflammatory cytotoxic response of microglia, the brain's tissue macrophages. However, the brain's innate immune system shows significant heterogeneity. Microglia participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review discusses the mechanisms that lead to reduction of self-toxicity and repair of the damaged extracellular matrix in the brain. Two partially overlapping and complementary macrophage states, alternative activation and acquired deactivation, are identified. These states are involved in immunosuppressive and repair processes, and their roles in chronic neuroinflammation in the brain are discussed. The innate immune response in the brain is characterized by the primary cells being microglia, although astrocytes and neurons may also play an immune role. Microglia recognize pathogens via pattern recognition receptors, including toll-like receptors, NOD proteins, and non-TLR receptors. These receptors interact with pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to initiate cellular defense mechanisms. Downstream signaling events begin with engagement of adaptor proteins, leading to activation of transcription factors and induction of proinflammatory genes. Classical activation is reduced by inherent feedback signals that regulate specific steps in the activation process. These signals include proteins that mediate ubiquitination and degradation of TLRs, competition between functional and nonfunctional adaptor proteins, and suppressor of cytokine signaling proteins. Noncoding RNA oligonucleotides (microRNAs) also regulate gene expression by binding to 3' untranslated regions of specific target genes. Repair and resolution involve changing the macrophage activation state from a proinflammatory to a gene profile that supports repair and tissue reconstruction. This switch is induced by multiple factors, including cytoactive agents and T_H2 regulatory cells. Anti-inflammatory cytokines, such as IL-4, IL-13, IL-10, and TGF-β, are the predominant induction signals. These cytokines antagonize classical activation pathways and induce new genes and proteins involved in tissue repair and reconstruction. Alternative activation (aaMac) is characterized by the absence and presence of specific genes whose expression levels change during the switch from a proinflammatory to an anti-inflammatory state. The term alternative activation is used to describe macrophages exposed primarily to IL-4 or IL-13. Acquired deactivation is another macrophage activation state that incorporates a mixed-phenotype population that exhibits immunosuppression and is associated with uptake of apoptotic cells. Acquired deactivation is distinguished by the type of induction agents and the functional changes associated with induction. The role of macrophage functional heterogeneity in chronic inflammation of the brain, particularly in Alzheimer's disease, is discussed. The review also covers the role of lectins and alternative activation, including the mannose receptor, and