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BACKGROUND:
Obesity-induced inflammation is a major cause of morbidity in a variety of disorders including atherosclerosis, cancer, and metabolic syndrome. In addition, obesity is a major risk factor for inflammatory dermatologic diseases, including atopic dermatitis and psoriasis. Recent studies have shown that obesity impairs lymphatic function. Since the lymphatic system is a critical regulator of inflammatory reactions, we tested the hypothesis that obesity-induced lymphatic dysfunction is a key regulator of cutaneous hypersensitivity reactions in obese mice.
METHODS:
We used a well-described diet-induced obesity (DIO) model and used mice fed a normal chow diet as a control. To assess cellular immunity, we induced contact hypersensitivity (CHS) responses in the ear using 1-fluoro-2,4-dinitrobenzene (DNFB). Responses were measured using histology and flow cytometry to analyze gross and cellular inflammatory responses, respectively. Finally, to test if improving lymphatic function results in enhanced resolution of inflammation in DIO mice, we injected recombinant human vascular endothelial growth factor-C (rhVEGF-C) into ears of DIO mice after induction of CHS with DNFB.
RESULTS:
In these experiments, obese mice had impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity. In addition, obese mice displayed heightened dermatitis responses to inflammatory skin stimuli, resulting in both higher peak inflammation and a delayed clearance of inflammatory responses. Injection of recombinant VEGF-C markedly increased lymphatic endothelial cell expression of CCL21 and decreased perilymphatic inducible nitrous oxide synthase (iNOS) accumulation, which resulted in increased lymphatic function, causing decreased dermatitis responses in both obese and control mice. Taken together, our findings suggest that obesity-induced changes in the lymphatic system result in an amplified and prolonged inflammatory response.
CONCLUSIONS:
This study is the first to show that DIO results in impaired lymphatic regulation of inflammation. We found that DIO results in exaggerated T cell inflammation and impaired T cell memory responses. These changes not only increase the intensity of inflammation, but more importantly impair its resolution in the setting of obesity. Finally, this study shows that by improving lymphatic function in DIO mice in the setting of CHS, the inflammatory responses are returned to a baseline, normal state. This finding is critical and suggests that pathologic changes in the lymphatic system may exacerbate and contribute to the wide-ranging pathologic responses to obesity.