Abstract
Anti-inflammatory cytokine interleukin (IL)-10 is pivotal for limiting excessive inflammation in the central nervous system. Reports show that lipopolysaccharide (LPS)-induced microglial IL-10 emerges in a delayed manner in vitro and in vivo, lagging behind proinflammatory cytokines to facilitate the resolution of neuroinflammation. We hypothesized that IL-10 releases quite quickly based on our pilot investigation. Here, we uncovered a bimodal expression of microglial IL-10 gene transcription induced by LPS in mouse primary mixed glial cultures. This pattern consisted of a short brief early-phase and a long-lived late-phase, enabling the production of IL-10 protein in a rapid manner. The removal and addition of IL-10 protein assays indicated that early-released IL-10 exerted potent modulatory effects on neuroinflammation at picomolar levels, and IL-10 released at the onset of neuroinflammation is tightly controlled. We further showed that the early-released, but not the late-released, IL-10 was crucial for mediating and potentiating the anti-inflammatory function of a β2-adrenergic receptor agonist salmeterol. This study in vitro highlights the essential role of early-released IL-10 in regulating the appropriate degree of neuroinflammation, overturning the previous notion that microglial IL-10 produces and functions in a delayed manner and providing new insights into anti-inflammatory mechanisms-mediated neuroimmune homeostasis.
Highlights
The appearance of the early peak of IL-10 expression occurred about the same time or earlier than that of TNFα, but far much earlier than that of IL-1β (Figure 1)
The late-phase IL-10 mRNA levels produced by LPS at 10 ng/mL were significantly lower than those by LPS at 1 μg/mL (Figure 1)
Bimodal increase in IL-10 mRNA expression was observed by both doses of LPS, which is different from the pattern of both TNFα and IL-1β (Figure 1)
Summary
Neuroinflammation plays a critical role in a variety of infectious and non-infectious disorders in the central nervous system (CNS), ranging from neurodegenerative diseases to mental disorders [1,2]. Dysregulated or persistent activation of microglia, the main immune cell in the brain, may lead to chronic low-grade neuroinflammation and neuronal damage [3]. One of the most important mechanisms limiting the detrimental effects of excessive neuroinflammation is to enhance the production of a potent anti-inflammatory cytokine interleukin-10 (IL-10). IL-10 is known to suppress the production of proinflammatory mediators through several mechanisms, such as destabilizing proinflammatory cytokine mRNA, negatively regulating Toll-like receptors (TLRs) signaling transduction, and inhibiting inflammasome activation [4,5,6]. IL-10 can protect tissues during inflammation by facilitating wound repair signaling [7,8]
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