The microglial "activation" continuum: from innate to adaptive responses

Abstract

Microglia are innate immune cells of myeloid origin that take up residence in the central nervous system (CNS) during embryogenesis. While classically regarded as macrophage-like cells, it is becoming increasingly clear that reactive microglia play more diverse roles in the CNS. Microglial "activation" is often used to refer to a single phenotype; however, in this review we consider that a continuum of microglial activation exists, with phagocytic response (innate activation) at one end and antigen presenting cell function (adaptive activation) at the other. Where activated microglia fall in this spectrum seems to be highly dependent on the type of stimulation provided. We begin by addressing the classical roles of peripheral innate immune cells including macrophages and dendritic cells, which seem to define the edges of this continuum. We then discuss various types of microglial stimulation, including Toll-like receptor engagement by pathogen-associated molecular patterns, microglial challenge with myelin epitopes or Alzheimer's beta-amyloid in the presence or absence of CD40L co-stimulation, and Alzheimer disease "immunotherapy". Based on the wide spectrum of stimulus-specific microglial responses, we interpret these cells as immune cells that demonstrate remarkable plasticity following activation. This interpretation has relevance for neurodegenerative/neuroinflammatory diseases where reactive microglia play an etiological role; in particular viral/bacterial encephalitis, multiple sclerosis and Alzheimer disease.

Figure 1

PAMP stimulation results in enhanced microglial phagocytosis. N9 cells (A) or primary cultured microglia from C57BL/6 mice (B) were pre-stimulated with the PAMPs indicated (Poly I:C, 50 μg/mL; LPS, 50 ng/mL; PGN, 50 μg/mL; CpG-DNA, 1 μM) for 6 hours. Cells were rinsed in complete RPMI 1640 media (containing 5% fetal calf serum and 1 mM penicillin/streptomycin) and then cultured for an additional 1 hour at 37°C or at 4°C (control) with yellow-green fluorescent latex beads (1:1000, Sigma). After extensive rinsing, microglia were subjected to fluorescence-activated cell sorter analysis, and mean fluorescence intensity of cells cultured at 4°C was subtracted from values from cells cultured at 37°C. These figures were then normalized to untreated control microglia to obtain percentage of phagocytosis increase over baseline. Unpaired t-test was used to assess statistical significance for each treatment condition compared to control, with n = 3 wells for each condition presented; ** p < 0.001, * p < 0.05. Abbreviations used: Poly (I:C), polyinosinic : polycytidylic acid; LPS, lipopolysaccharide; PGN, peptidoglycan; CpG-DNA, unmetylated DNA containing CpG motifs.

Figure 2

Model for innate versus adaptive microglial activation responses. In the context of β-amyloid challenge, microglia activate a phagocytic response. If co-stimulated with CD40 ligand, a shift from innate activation to adaptive antigen-presenting cell response ensues. Additionally, certain anti-inflammatory Th2-type cytokines shift this balance back towards innate phagocytic response, while some pro-inflammatory Th1-associated cytokines tip the balance further towards adaptive activation of microglia. See the text and Table 1 for references. Abbreviations used: APC, antigen presenting cell; CD40L, CD40 ligand; Th1, CD4+ T helper cell type I response; Th2, Th type II response; TGF, transforming growth factor; IL, interleukin; IFN, interferon, TNF, tumor necrosis factor.