The lymphatic transport has important roles in coordinating local immune responses. The biological effects on tissue inflammation following lymphatic flow obstruction in vivo, however, are not fully understood. In this study, to further investigate the in vivo role of lymphatic system in skin inflammation, we induced psoriasis-like inflammation on mouse back skin or ear with topical application of imiquimod (IMQ), using k-cyclin transgenic (kCYC+/-) mice, which demonstrate severe lymphatic dysfunction. kCYC+/- mice showed severe clinical scores and enhanced ear swelling to IMQ treatment compared with wild-type littermates. Immunohistochemistry showed increased epidermal thickness. On the other hand, mRNA expression levels of inflammatory cytokines including IFN-γ, TNF-α, and IL-17A, in IMQ-treated skin were comparable between kCYC+/- mice and wild-type mice. Interestingly, western blot analyses revealed that protein expression levels of IFN-γ, TNF-α, IL-17A, IL-22, and IL-23 were significantly upregulated in IMQ-treated skin of kCYC+/- mice compared to wild-type mice. Consistently, phosphorylation of STAT3, which can be induced by IL-17 and IL-22 and associated with epidermal hyperplasia, was also augmented in epidermal keratinocytes in IMQ-treated skin of kCYC+/- mice. These results suggest that lymphatic dysfunction in kCYC+/- mice caused accumulation of inflammatory cytokine proteins without upregulation of mRNA expressions, resulting in exacerbation of IMQ-induced psoriasis-like skin inflammation. The findings add insight into the clinical problem of inflammatory dermatitis that commonly occurs in humans with peripheral edema of the lower legs.

Lymphatic flow blockade amplifies inflammation in imiquimod-induced psoriasis-like skin lesions.