Impaired Meningeal Lymphatic Drainage Aggravates LPS‐Induced Neuroinflammation and Depression‐Like Behaviors in Mice

<b>Background:</b> The role of meningeal lymphatic vessels (mLVs) in neurodegenerative diseases has been increasingly recognized. However, their involvement in lipopolysaccharide (LPS)-induced neuroinflammation and associated depression-like behaviors remains poorly understood. Given that impaired clearance of neurotoxic substances can prolong central nervous system (CNS) inflammation, investigating the function of mLVs in this context may offer new insights into the mechanisms underlying acute neuroinflammation and provide potential therapeutic targets. <b>Methods:</b> First, the impact of intracerebral injection of LPS on the function of mLVs was investigated. Subsequently, the MAZ51, a VEGFR3 antagonist, was administered via intraperitoneal injection for 1 month to inhibit the development and function of mLVs, and to evaluate whether the impaired drainage function of mLVs exacerbates inflammation in the CNS caused by LPS. Finally, VEGFR3 ligand VEGF-C was administered preemptively to assess whether enhancing the function of mLVs mitigates LPS-induced inflammation and depression-like behavior. <b>Results:</b> The mice with intracerebral injection of LPS demonstrated a substantial reduction in the transport of OVA-647 to the deep cervical lymph nodes (dCLNs) and in the coverage of Lyve-1 within the mLVs, suggesting LPS impaired the development and drainage of mLVs. Pretreatment with MAZ51 further damages the drainage function of mLVs and intensify LPS-induced activation of microglia and astrocytes. Additionally, MAZ51 led to a decrease in the protein levels of PSD95 as well in the hippocampus, which was paralleled by an elevation in TNF-α and IL-6 levels, and aggravated depression-like behavior. On the contrary, pretreatment with VEGFR3 ligand VEGF-C attenuated LPS-induced neuroinflammation, as indicated by a decrease in TNF-α, IL-6, Iba1, and GFAP expression in the hippocampus. VEGF-C treatment also significantly increased the level of PSD95 and improved depression-like behavior. <b>Conclusion:</b> The drainage function of mLVs is pivotal in inflammation of the CNS. Enhancing meningeal lymphatic improves the development of neuroinflammation and inflammation-induced depression-like behaviors. VEGFR3 could serve as a potential therapeutic target for CNS inflammation.