TNF-alpha regulates corneal Langerhans cell migration

Langerhans cells (LC) belong to the dendritic cell family and mediate Ag presentation in the cornea and ocular surface. Under normal physiological conditions, the central cornea is devoid of LC. Centripetal migration of LC plays a critical role in promoting immunoinflammatory responses in the eye including allograft rejection and herpetic keratitis. The molecular mechanisms responsible for ocular LC migration are poorly understood. To examine whether TNF-alpha mediates corneal LC migration and to establish the interaction of IL-1 and TNF-alpha in regulating LC migratory capacity, we utilized gene-targeted knockout mice lacking IL-1 receptor I (IL-1RI-/-), TNF receptor I (p55-/-), TNF receptor II (p75-/-), or both (p55-/-p75-/-). LC migration was induced by thermal cautery or cytokine injection and enumerated by an immunofluorescence assay. Migration of LC after cauterization and TNF-alpha injection was significantly depressed in both p55-/- and p75-/- mice. Similarly, in the first 72 h after intracorneal injection of IL-1alpha, LC migration was reduced in p55-/-, p75-/-, and p55-/-p75-/- mice. In contrast, injection of TNF-alpha in IL-1RI-/- mice led to normal migration of corneal LC indistinguishable from wild-type controls. These results suggest that the IL-1 induction of corneal LC migration is largely mediated by TNFR function, whereas TNF-alpha induction of LC migration is independent of IL-1RI activity. Moreover, the data suggest that both p55 and p75 signaling pathways are important in mediating LC migration in the cornea.