SUMMARY Basal cell carcinoma (BCC) is characterized by frequent loss of PTCH1, leading to constitutive activation of the Hedgehog pathway. Although the requirement for Hedgehog in BCC is well-established, the identity of disease-initiating cells and the compartments in which they reside remain controversial. By using several inducible Cre drivers to delete Ptch1 in different cell compartments in mice, we show here that multiple hair follicle stem cell populations readily develop BCC-like tumors. In contrast, stem cells within the interfollicular epidermis do not efficiently form tumors. Notably, we observed that innervated Gli1-expressing progenitors within mechanosensory touch dome epithelia are highly tumorigenic. Sensory nerves activate Hedgehog signaling in normal touch domes, while denervation attenuates touch dome-derived tumors. Together, our studies identify varying tumor susceptibilities among different stem cell populations in the skin, highlight touch dome epithelia as “hot spots” for tumor formation, and implicate cutaneous nerves as mediators of tumorigenesis.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Recent studies suggest diverse mechanisms underlying demyelination, including a subset of lesions involving interplay between metabolic insult to oligodendrocytes and inflammatory mediators. For mice of susceptible strains, cuprizone feeding results in oligodendrocyte cell loss and demyelination of the corpus callosum. Remyelination ensues, and has been extensively studied. Cuprizone-induced demyelination remains incompletely characterized. Here we show that mice lacking type 2 CXC chemokine receptor (CXCR2) are relatively resistant to cuprizone-induced demyelination, and CXCR2+ neutrophils from the circulation play an essential role in cuprizone-induced demyelination. Findings support a novel two-hit process of cuprizone-induced demyelination, mirroring proposals about pathogenesis of MS lesions featuring extensive oligodendrocyte cell loss. These data indicate that cuprizone-induced demyelination will provide a useful model for certain aspects of MS pathogenesis.

Nervous system involvement in psoriasis pathogenesis is supported by increases in nerve fiber numbers and neuropeptides in psoriatic skin and by reports detailing spontaneous plaque remission following nerve injury. Using the KC-Tie2 psoriasisform mouse model, we investigated the mechanisms by which nerve injury leads to inflammatory skin disease remission. Cutaneous nerves innervating dorsal skin of KC-Tie2 animals were surgically axotomized and beginning 1d following denervation, CD11c+ cell numbers decreased by 40% followed by a 30% improvement in acanthosis at 7d and a 30% decrease in CD4+ T cell numbers by 10d. Restoration of SP signaling in denervated KC-Tie2 skin prevented decreases in CD11c+ and CD4+ cells but had no affect on acanthosis; restoration of CGRP signaling reversed the improvement in acanthosis and prevented denervated-mediated decreases in CD4+ cells. Under innervated conditions, small molecule inhibition of SP in KC-Tie2 animals resulted in similar decreases to those observed following surgical denervation for cutaneous CD11c+ and CD4+ cell numbers; whereas small molecule inhibition of CGRP resulted in significant reductions in CD4+ cell numbers and acanthosis. These data demonstrate that sensory nerve-derived peptides mediate psoriasiform dendritic cell and T cell infiltration and acanthosis and introduce targeting nerve-immunocyte/keratinocyte interactions as potential psoriasis therapeutic treatment strategies.

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of pro-inflammatory transcripts with concomitant induction of anti-inflammatory genes including Ptgds and Hsd11b1. Finally, triterpenoids induced oligodendrocyte maturation in vitro and enhanced myelin repair in an LPC-induced non-inflammatory model of demyelination in vivo. These results demonstrate the unique potential of triterpenoid derivatives for the treatment of neuroinflammatory disorders such as MS.

The mechanisms underlying developmental myelination have therapeutic potential following CNS injury and degeneration. We report that transplanted central glial (