The novel role of lymphatic vessels in the pathogenesis of ocular diseases.

Historically, the eye has been considered as an organ free of lymphatic vessels. In recent years, however, it became evident, that lymphatic vessels or lymphatic-like vessels contribute to several ocular pathologies at various peri- and intraocular locations. The aim of this review is to outline the pathogenetic role of ocular lymphatics, the respective molecular mechanisms and to discuss current and future therapeutic options based thereon. We will give an overview on the vascular anatomy of the healthy ocular surface and the molecular mechanisms contributing to corneal (lymph)angiogenic privilege. In addition, we present (i) current insights into the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea triggered e.g. by inflammation or trauma, (ii) the role of lymphatic vessels in different ocular surface pathologies such as dry eye disease, corneal graft rejection, ocular graft versus host disease, allergy, and pterygium, (iii) the involvement of lymphatic vessels in ocular tumors and metastasis, and (iv) the novel role of the lymphatic-like structure of Schlemm's canal in glaucoma. Identification of the underlying molecular mechanisms and of novel modulators of lymphangiogenesis will contribute to the development of new therapeutic targets for the treatment of ocular diseases associated with pathological lymphangiogenesis in the future. The preclinical data presented here outline novel therapeutic concepts for promoting transplant survival, inhibiting metastasis of ocular tumors, reducing inflammation of the ocular surface, and treating glaucoma. Initial data from clinical trials suggest first success of novel treatment strategies to promote transplant survival based on pretransplant corneal lymphangioregression.

Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor regulating adaptive and maladaptive responses toward exogenous and endogenous signals. Research from various biomedical disciplines has provided compelling evidence that the AHR is critically involved in the pathogenesis of a variety of diseases and disorders, including autoimmunity, inflammatory diseases, endocrine disruption, premature aging and cancer. Accordingly, AHR is considered an attractive target for the development of novel preventive and therapeutic measures. However, the ligand-based targeting of AHR is considerably complicated by the fact that the receptor does not always follow the beaten track, i.e. the canonical AHR/ARNT signaling pathway. Instead, AHR might team up with other transcription factors and signaling molecules to shape gene expression patterns and associated physiological or pathophysiological functions in a ligand-, cell- and micromilieu-dependent manner. Herein, we provide an overview about some of the most important non-canonical functions of AHR, including crosstalk with major signaling pathways involved in controlling cell fate and function, immune responses, adaptation to low oxygen levels and oxidative stress, ubiquitination and proteasomal degradation. Further research on these diverse and exciting yet often ambivalent facets of AHR biology is urgently needed in order to exploit the full potential of AHR modulation for disease prevention and treatment.

Keratinocytes Counteract UVB-Induced Immunosuppression in Mice through HIF-1a Signaling.

The transcription factor HIF-1a regulates cellular metabolism under hypoxia but also immune responses and UVB-induced skin reactions. In keratinocytes (KCs), HIF-1a is an environmental sensor orchestrating the adaptation to environmental changes. In this study, we investigated the role of HIF-1a in KCs for skin reactions to acute and chronic UVB exposure in mice. The function of HIF-1a in KCs under UVB exposure was analyzed in KC-specific HIF-1a conditional knockout (cKO) mice. cKO mice were hypersensitive to acute high-dose UVB irradiation compared with wild-type mice, displaying increased cell death and delayed barrier repair. After chronic low-dose UVB treatment, cKO mice also had stronger epidermal damage but reduced infiltration of dermal macrophages and T helper cells compared with wild-type mice. Irradiated cKO mice revealed accumulation of regulatory lymphocytes in dorsal skin-draining lymph nodes compared with wild-type and unirradiated mice. This was reflected by an augmented IL-10 release of lymph node cells and a weaker contact hypersensitivity reaction to DNFB in UVB-exposed cKO mice than in wild-type and unirradiated controls. In summary, we found that KC-specific HIF-1a expression is crucial for adaptation to UVB exposure and inhibits the development of UVB-induced immunosuppression in mice. Therefore, HIF-1a signaling in KCs could ameliorate photoaging-related skin disorders.