Evidence indicates that C-Chemokine Receptor 7 (CCR7) is implicated in behavioral dysfunction and that chlorogenic acid (CGA) exerts beneficial effects on cognitive deficits. However, the precise mechanisms by which CCR7 regulates cognitive dysfunction and whether CGA exerts its therapeutic effects through modulation of CCR7 signaling remain to be elucidated. Here, we investigated the specific role and mechanism of CCR7 on LPS-induced cognitive deficits using wild type (WT) and CCR7 knockout (CCR7−/−) mice, and assessed the protective effect of CGA against these deficits. We found intracerebroventricular (i.c.v.) injection of LPS in WT mice induced learning and behavioral deficits in the open field test and Morris water maze (MWM) task, which were ameliorated in LPS-treated CCR7−/− mice. Furthermore, we observed increased expression of the anti-apoptotic marker Bcl-2 and synaptic markers (PSD95, SYN) in the hippocampus of LPS-treated CCR7−/− mice compared to that in LPS-stimulated WT mice. One potential mechanism of this action was attributed to the inhibition of LPS-induced, CCR7-mediated astrocyte activation, which was accompanied by reduced activation of its downstream proinflammatory signaling pathways (NF-κB, p38 and JNK) and the decreased production of pro-inflammatory factors including COX-2, iNOS, TNF-α, IL-1β and IL-6 in the hippocampus of LPS-treated CCR7−/− mice. Importantly, we demonstrated CGA ameliorated LPS-induced cognitive dysfunction, at least in part, through inhibition of CCR7-mediated astrocyte activation and its downstream NF-κB, p38 and JNK pathway activation. Collectively, precise elucidation of the inhibitory effect of CGA on CCR7 signaling in LPS-stimulated mice contributes to the development of strategies for controlling neuroinflammation-mediated cognitive disorders.
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