Abstract
Simple SummaryIn this study we investigated how neuron-derived extracellular vesicles (NDEVs) mediate neuroimmune regulation in primary cell culture systems. Rat cortical neurons released EVs that improved microglial survival and inhibited the expression of activation markers on microglia. Furthermore, NDEVs reduced the LPS-induced proinflammatory response and promoted an anti-inflammatory response. Thus, neurons critically regulate microglia activity and control inflammation via EV-mediated neuron–glia communication.Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of neuron-derived EVs (NDEVs) on microglia, NDEVs were isolated from the culture supernatant of rat cortical neurons. When NDEVs were added to primary cultured rat microglia, we found significantly improved microglia viability via inhibition of apoptosis. Additionally, application of NDEVs to cultured microglia also inhibited the expression of activation surface markers on microglia. Furthermore, NDEVs reduced the LPS-induced proinflammatory response in microglia according to reduced gene expression of proinflammatory cytokines (TNF-α, IL-6, MCP-1) and iNOS, but increased expression of the anti-inflammatory cytokine, IL-10. These findings support that neurons critically regulate microglia activity and control inflammation via EV-mediated neuron–glia communication. (Supported by R21AA025563 and R01AA025591).
Highlights
Microglia, one of three types of glial cells found in the central nervous system (CNS), though of myeloid origin [1], act as the brain’s primary immune cells
NTA revealed that S-extracellular vesicles (EVs) secreted from neurons were 158.3 ± 75.9 nm in size, with a peak diameter of about 106 nm (Figure 1A)
Our results showed that extracellular particles with the characteristics of EVs are involved in neuron-to-microglia communication and may deliver cargo from neurons to microglia as evidenced by the functional change of microglia after Small EVs (S-EVs) treatment
Summary
One of three types of glial cells found in the CNS, though of myeloid origin [1], act as the brain’s primary immune cells. Proinflammatory activated “M1-like” microglia produce cytokines, chemokines and radical species, which contribute to brain inflammation and further brain damage [5,6]. “M2-like” microglia, produce anti-inflammatory cytokines and growth factors that are associated with reparative processes or resolution of damage [6]. Both the quiescent and activated states of microglia are controlled by cell-autonomous mechanisms, such as epigenetic, microRNA and other extracellular signals [2]. In addition to providing inhibitory signals through the secretion of soluble factors or cell-to-cell contact, neurons release extracellular vesicles (EVs) that play an important role in neuron–glia communication [10,11,12]
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