Acute and chronic nasal inflammation induces lymphangiogenesis in the olfactory mucosa in mice.

Background: Lymphangiogenesis, the formation of new lymphatic vessels, is primarily driven by VEGF-C-mediated activation of VEGFR-3 and plays a critical role in immune regulation and tissue repair. Although lymphangiogenesis has been well documented in various inflamed tissues, its occurrence and spatiotemporal characteristics in the olfactory mucosa during nasal inflammation remain poorly understood. To address this, we investigated the localization and development of lymphatic vessels in a mouse model of both acute and chronic nasal inflammation. Methods: Acute inflammation was induced by intranasal administration of lipopolysaccharide (LPS; 10 μg per nostril) in 8-week-old male mice, with saline-treated mice as controls. Behavioral tests were conducted at 24 and 48 h post-administration. Nasal tissues were collected at multiple time points up to four weeks. Cytokine expression was analyzed by quantitative RT-PCR, and VEGF levels were quantified using ELISA. Immune cell infiltration and lymphatic vessel localization were assessed histologically using markers such as Lyve-1, VEGFR-3, and Prox-1. For the chronic inflammation model, mice received unilateral intranasal LPS or saline administration three times per week for 10 weeks, followed by histological analysis of lymphatic remodeling. Results: Mice showed transient reduction in food and water intake and body weight, some aspects of sickness behavior within 24 h, but did not display depression-like phenotypes at 24 and 48 h post-LPS, as measured by duration of immobility in the tail suspension test and forced swim test, and percent sucrose volume consumed in the sucrose preference test. LPS treatment induced a sustained inflammatory response, with elevated pro- and anti-inflammatory cytokine expression persisting for up to two weeks. Immune cell infiltration and lymphangiogenesis were localized to specific areas of the olfactory mucosa, particularly the inner regions of the first and second turbinates. These inflammatory hotspots exhibited increased expression of lymphatic markers, primarily due to proliferation of lymphatic endothelial cells. VEGF-C and VEGF-A levels were significantly upregulated following LPS treatment. In the chronic model, lymphangiogenesis became more widespread throughout the olfactory mucosa, and was accompanied by dense infiltration of CD11b + immune cells. Conclusions: Nasal inflammation induces region-specific lymphangiogenesis during the acute phase, likely driven by local proliferation of lymphatic endothelial cells. Under chronic inflammatory conditions, both inflammation and lymphangiogenesis expand across the olfactory mucosa. Further studies are needed to elucidate the underlying molecular mechanisms and to determine the functional relevance of olfactory lymphangiogenesis.