Abstract
Interleukin (IL)-4 is a cytokine that affects both adaptive and innate immune responses. In the central nervous system, microglia express IL-4 receptors and it has been described that IL-4-exposed microglia acquire anti-inflammatory properties. We here demonstrate that IL-4 exposure induces changes in the cell surface protein expression profile of primary rhesus macaque microglia and enhances their potential to induce proliferation of T cells with a regulatory signature. Moreover, we show that Toll like receptor (TLR)-induced cytokine production is broadly impaired in IL-4-exposed microglia at the transcriptional level. IL-4 type 2 receptor-mediated signaling is shown to be crucial for the inhibition of microglial innate immune responses. TLR-induced nuclear translocalization of NF-κB appeared intact, and we found no evidence for epigenetic modulation of target genes. By contrast, nuclear extracts from IL-4-exposed microglia contained significantly less NF-κB capable of binding to its DNA consensus site. Further identification of the molecular mechanisms that underlie the inhibition of TLR-induced responses in IL-4-exposed microglia may aid the design of strategies that aim to modulate innate immune responses in the brain, for example in gliomas.
Highlights
Interleukin (IL)-4 is well known for its biological functions during humoral and cell-mediated adaptive immune responses
As the cell surface expression profile of IL-4-exposed microglia differed most notably for molecules implicated in the process of antigen presentation, we assessed the functional consequences of this altered expression profile by measuring the potential of IL-4exposed microglia to stimulate T cell proliferation of Mamu-DR non-matching donor monkeys in mixed lymphocyte reactions (MLR)
We demonstrate that exposure of primary adult rhesus monkey microglia to IL-4 affects their cell surface protein expression profile as well as their potential to induce the proliferation of T cells with a regulatory signature, which is largely in line with earlier studies [8, 24, 34,35,36]
Summary
Interleukin (IL)-4 is well known for its biological functions during humoral and cell-mediated adaptive immune responses. It stimulates the proliferation of activated B and T cells, it is pivotal for the differentiation of B cells into plasma cells and it skews T cell-mediated cytokine production [1]. IL-4 exerts effects on cells of the innate immune system. It is important for the differentiation of monocyte-derived dendritic cells (DC), it enhances MHC class II expression levels and it promotes the alternative activation of macrophages, while inhibiting classical activation [2, 3]. Its production can be induced in astrocytes and microglia [7,8,9], that both have
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