Abstract
Cytokines are important neuroinflammatory modulators in neurodegenerative brain disorders including traumatic brain injury (TBI) and stroke. However, their temporal effects on the physiological properties of microglia and neurons during the recovery period have been unclear. Here, using an ATP-induced cortical injury model, we characterized selective effects of ATP injection compared to needle-control. In the damaged region, the fluorescent intensity of CX3CR1-GFP (+) cells, as well as the cell density, was increased and the maturation of newborn BrdU (+) cells continued until 28 day-post-injection (dpi) of ATP. The excitability and synaptic E/I balance of neurons and the inward and outward membrane currents of microglia were increased at 3 dpi, when expressions of tumor necrosis factor (TNF)-α/interleukin (IL)-1β and IL-10/IL-4 were also enhanced. These changes of both cells at 3 dpi were mostly decayed at 7 dpi and were suppressed by any of IL-10, IL-4, suramin (P2 receptor inhibitor) and 4-AP (K+ channel blocker). Acute ATP application alone induced only small effects from both naïve neurons and microglial cells in brain slice. However, TNF-α alone effectively increased the excitability of naïve neurons, which was blocked by suramin or 4-AP. TNF-α and IL-1β increased and decreased membrane currents of naïve microglia, respectively. Our results suggest that ATP and TNF-α dominantly induce the physiological activities of 3 dpi neurons and microglia, and IL-10 effectively suppresses such changes of both activated cells in K+ channel- and P2 receptor-dependent manner, while IL-4 suppresses neurons preferentially.
Highlights
IntroductionMicroglia are the innate immune cells in the brain which engage and respond to brain injury and infection by releasing various inflammatory cytokines, such as TNFα, IL-1β, IL-6, IL-18, IL-12, interferon-γ, IL-4, IL-10, and transforming growth factor-β
Microglia are the innate immune cells in the brain which engage and respond to brain injury and infection by releasing various inflammatory cytokines, such as TNFα, IL-1β, IL-6, IL-18, IL-12, interferon-γ, IL-4, IL-10, and transforming growth factor-β.They respond to cytokines by their cognate receptors and affect neuronal functions during development and in many brain diseases [1,2,3,4,5,6,7,8,9,10]
We found that exogenous ATP was necessary for the microglia activation compared to needle-controls after the injury, and the sequential dominant actions of tumor necrosis factor (TNF)-α and anti-inflammatory cytokines seemed to explain most temporal physiological changes observed in microglia and neurons, where the activities of both P2 receptors and K+ ion channels were critical
Summary
Microglia are the innate immune cells in the brain which engage and respond to brain injury and infection by releasing various inflammatory cytokines, such as TNFα, IL-1β, IL-6, IL-18, IL-12, interferon-γ, IL-4, IL-10, and transforming growth factor-β. They respond to cytokines by their cognate receptors and affect neuronal functions during development and in many brain diseases [1,2,3,4,5,6,7,8,9,10]. It will be important to find out whether any functional effects of cytokines on both cell types are constant or variable depending on the dose or the time course of the injury state, which reflects niche conditions
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