Synthetic host defence peptides modulate phagocytic activity and release of inflammatory mediators by BV-2 microglial...

Microglia are the predominant resident innate immune cells of the brain that maintain homeostasis and mitigate damage caused by injury and pathogens. Synthetic variants of host defence peptides, also termed antimicrobial peptides, are designed based on their endogenous counterparts and have been demonstrated to exhibit enhanced immunomodulatory activities, including an ability to selectively modulate the release of cytokines by monocytic cells. These peptides exert therapeutic benefits in a murine brain injury model, but it is unknown whether they can modulate microglial immune responses. We tested the effects of three host defence peptides, namely innate defence regulators (IDR)-1002, IDR-1018 and D-3006, on selected functions of BV-2 murine microglial cells, as well as differentiated HL-60 monocytic cells, which were used as a human model of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production. It was demonstrated here that IDR-1002, IDR-1018 and D-3006 reduced the production of nitric oxide, tumor necrosis factor-α (TNF), ROS, and cytotoxic factors, depending on whether the cells were stimulated with lipopolysaccharide (LPS), interferon (IFN)-γ, or their combination. All three IDRs also reduced LPS-induced phagocytic activity of BV-2 microglia, while IDR-1018 and D-3006 increased this function in unstimulated cells, though our findings are limited to cell lines and require validation in primary or human microglia. By altering selected inflammatory, cytotoxic, and phagocytic readouts of microglial cells in a context-dependent manner, synthetic host defence peptides such as IDRs warrant further investigation as candidate modulators of neuroinflammation, including in animal models of relevant neurological disorders.