We report here that the leptomeningeal cells transduce inflammatory signals from peripheral macrophages to brain-resident microglia in response to Porphyromonas gingivalis (P.g.) LPS. The expression of Toll-like receptor 2 (TLR2), TLR4, TNF-α, and inducible NO synthase was mainly detected in the gingival macrophages of chronic periodontitis patients. In in vitro studies, P.g. LPS induced the secretion of TNF-α and IL-1β from THP-1 human monocyte-like cell line and RAW264.7 mouse macrophages. Surprisingly, the mean mRNA levels of TNF-α and IL-1β in leptomeningeal cells after treatment with the conditioned medium from P.g. LPS-stimulated RAW264.7 macrophages were significantly higher than those after treatment with P.g. LPS alone. Furthermore, the mean mRNA levels of TNF-α and IL-1β in microglia after treatment with the conditioned medium from P.g. LPS-stimulated leptomeningeal cells were significantly higher than those after P.g. LPS alone. These observations suggest that leptomeninges serve as an important route for transducing inflammatory signals from macrophages to microglia by secretion of proinflammatory mediators during chronic periodontitis. Moreover, propolis significantly reduced the P.g. LPS-induced TNF-α and IL-1 β production by leptomeningeal cells through inhibiting the nuclear factor-κB signaling pathway. Together with the inhibitory effect on microglial activation, propolis may be beneficial in preventing neuroinflammation during chronic periodontitis. 1. Introduction Periodontitis is the most common adult chronic inflammatory disorder, which results in a consequence of the persistent systemic inflammatory responses [1, 2]. Porphyromonas gingivalis (P.g.) is the major periodontopathic bacteria [3, 4], and its LPS (P.g. LPS) is thought to induce periodontitis through Toll-like receptors, TLR2 or TLR4 [5]. As the main population in inflammatory oral mucosa, macrophages are known to determine P.g. LPS-induced oral innate immune responses through TLRs during chronic periodontitis [5, 6]. Macrophages can be polarized into M1 and M2 phenotypes depending on the microenvironment [7]. M1 macrophages promote inflammation and tissue damage by secreting proinflammatory mediators, including TNF-α, IL-1β, and expressing inducible NO synthase (iNOS). In contrast, M2 macrophages promote anti-inflammation and wound healing by secreting anti-inflammatory mediators, including IL-10 and TGF-β1, and upregulating arginase 1 (Arg 1) [8, 9]. In addition to causing chronic systemic inflammatory diseases, including atherosclerosis, cardiovascular disease, and
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