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Figure 1 | Molecular Neurodegeneration

Figure 1

From: Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD)

Figure 1

Modulation of Microglia Phenotypes in HIV associated dementia (HAD). The roles of microglia include phagocytosis, antigen presentation, as well as generation and excretion of cytokines, eicosanoids, complement components, and excitatory amino acids (EAA) including, glutamate, quinolinic acid (QUIN), oxidative radicals, and nitric oxide (NO) [2]. At least three phenotypic states of microglia exist based on developmental and pathophysiologic studies: (i) resting, ramified; (ii) activated non-phagocytic (or APC like) found in areas involved in central nervous system (CNS) inflammation; and (iii) reactive, phagocytic micorglia observed in areas of trauma or infection [37]. In regard to activation, these cells are able to polarize into two major subtypes: M1 or M2 [8, 9]. M1 subtype over-produces pro-inflammatory cytokines. It is marked by production of high levels of interferon -gamma (IFN-γ) tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-12, and low levels of IL-10 [8, 9]. The M1 phenotype may be activated when microglia contact HIV proteins (such as transactivator of transcription [Tat]) [10] or bind toll-like receptors 3 or 4 as well [11]. M2 microglia dampen inflammation, become phagocytic, and produce very low levels of TNF-α, IL-1, IL-12 and high amounts of anti-inflammatory IL- 10 and transforming growth factor (TGF)-β, and SOCS (suppressor of cytokine signaling) [12, 13]. These two phenotypes, respectively, correspond to the type ii or iii microglial states described in the preceding paragraph. Further, the factors which cause polarization to M1 or M2, reinforce the maintenance of that phenotype in a cycle-like manner [8, 9] (Figure 1). Increased M1 polarization is consistent with increased TNF-α observed in plasma and brain specimens in HAD and AD, and may play a role in the pathophysiology of both diseases [14]. Stimulation of Th1 and Th2 immune response by microglia is dependent upon the expression of specific molecules including major histocompatibility complex (MHC) II and CD40 [15]. v = viral factors ~ = soluble or cell surface receptor ligation Δ = cytokines and soluble factors

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