Vitiligo Skin T Cells Are Prone to Produce Type 1 and Type 2 Cytokines to Induce Melanocyte Dysfunction and Epidermal Inflammatory Response Through Jak Signaling.

Vitiligo is a T cell-mediated inflammatory skin disorder characterized by the loss of epidermal melanocytes. However, the contribution of melanocytes to the physiopathology of the disease in response to the T-cell microenvironment remains unclear. Here, using NanoString technology and multiplex ELISA, we show that active vitiligo perilesional skin is characterized by prominent type 1 and 2 associated immune responses. The vitiligo skin T-cell secretome downregulated melanocyte function and adhesion while increasing melanocyte mitochondrial metabolism and expression of inflammatory cytokines and chemokines by epidermal cells. The Jak1/2 inhibitor ruxolitinib strongly inhibited such effects on epidermal cells. Our data highlight that vitiligo is more complex than previously thought, with prominent combined activities of both T helper type 1- and T helper type 2-related cytokines inducing inflammatory responses of epidermal cells. Melanocytes do not appear only to be a target of T cells in vitiligo but could actively contribute to perpetuate inflammation. Jak inhibitors could prevent the impact of T cells on epidermal cells and pigmentation, highlighting their potential clinical benefit in vitiligo.

UVB-induced DHODH upregulation, which is driven by STAT3, is a promising target for chemoprevention and combination therapy of photocarcinogenesis.

The leading cause of cutaneous squamous cell carcinomas (cSCCs) is exposure to ultraviolet radiation (UV). Unlike most other cancers, the incidence rates of cSCCs are still on the rise and the treatment options currently available are limited. We have recently found that dihydroorotate dehydrogenase (DHODH), which is the rate-limiting enzyme in the de novo pyrimidine synthesis pathway, plays a critical role in UVB-induced energy metabolism reprogramming. Using a multistage model of UVB radiation-induced skin cancer, we show that UVB-induced DHODH upregulation is mainly regulated transcriptionally by STAT3. Our results indicate that chronic inhibition of DHODH by leflunomide (LFN) blocks UVB-induced tumor initiation. Human tumor xenograft studies showed that LFN treatment reduces growth of established tumors when used in combination with a genotoxic agent, 5-fluorouracil (5-FU). Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.

Lacteal junction zippering protects against diet-induced obesity.

Excess dietary lipid uptake causes obesity, a major global health problem. Enterocyte-absorbed lipids are packaged into chylomicrons, which enter the bloodstream through intestinal lymphatic vessels called lacteals. Here, we show that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of Neuropilin1 (Nrp1) and Vascular endothelial growth factor receptor 1 (Vegfr1; also known as Flt1) renders mice resistant to diet-induced obesity. Absence of NRP1 and FLT1 receptors increased VEGF-A bioavailability and signaling through VEGFR2, inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by VEGFR2 and vascular endothelial (VE)-cadherin signaling inhibition rescued chylomicron transport in the mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal VE-cadherin anchors prevented chylomicron uptake in wild-type mice. These data suggest that lacteal junctions may be targets for preventing dietary fat uptake.