Expression and localization of Yap and Taz during development of the mandibular first molar in rats.

Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are two downstream factors in the Hippo signaling pathway. Yap and Taz participate in regulating organ size, stem cell self-renewal, proliferation and differentiation. We investigated the spatial-temporal expression and relative expression levels of Yap and Taz using immunohistochemistry and real-time polymerase chain reaction. We found Yap and Taz in the oral epithelium and mesenchyme at embryonic (E) day 14.5 (E14.5) and E16.5. By E18.5, Yap and Taz were detected in the dental papilla and the entire enamel organ. At postnatal (P) day 0 (PN0), PN3 and PN7, Yap and Taz expression was localized in ameloblasts, odontoblasts and stratum intermedium. Yap and Taz were expressed in Hertwig's epithelial root sheath (HERS) at PN7. At PN3, PN7 and PN14, Yap was detected in the enamel matrix. From PN21 to PN28, Yap and Taz were absent from differentiated ameloblasts, but they were expressed in odontoblasts. From PN0 to PN10, the Yap and Taz mRNA expression increased, then decreased. We found that Yap and Taz may influence the differentiation of ameloblasts and odontoblasts; they also may contribute to enamel mineralization, crown morphogenesis and root formation.

Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation.

Inflammatory damage of mucosal surface of the eye is a hallmark of dry eye disease (DED) and, in severe cases, can lead to significant discomfort, visual impairment, and blindness. DED is a multifactorial autoimmune disorder with a largely unknown pathogenesis. Using a cross-sectional patient study and a well-characterized murine model of DED, herein we investigated the immunoregulatory function of interleukin-22 (IL-22) in the pathogenesis of DED. We found that IL-22 levels were elevated in lacrimal fluids of DED patients and inversely correlated with severity of disease. Acinar cells of the lacrimal glands (LGs), not inflammatory immune cells, are the primary source of IL-22, which suppresses inflammation in ocular surface epithelial cells upon desiccating stress. Moreover, loss of function analyses using IL-22 knockout mice demonstrated that IL-22 is essential for suppression of ocular surface infiltration of Th17 cells and inhibition of DED induction. Our novel findings elucidate immunoregulatory function of LG-derived IL-22 in inhibiting IL-17-mediated ocular surface epitheliopathy in DED thus making IL-22 a new relevant therapeutic target.

Activation of HIF-1α (hypoxia inducible factor-1α) prevents dry eye-induced acinar cell death in the lacrimal gland.

The pathogenesis of immune-mediated lacrimal gland (LG) dysfunction in Sjögren's syndrome has been thoroughly studied. However, the majority of dry eye (DE) is not related to Sjögren type, and its pathophysiology remains unclear. The purpose of this study was to determine and investigate the protective mechanisms against DE stress in mice. DE induced prominent blood vessel loss without apoptosis or necrosis in the LG. Autophagic vacuoles, distressed mitochondria, and stressed endoplasmic reticulum were observed via electron microscopy. Immunoblotting confirmed the increase in autophagic markers. Glycolytic activities were enhanced with increasing levels of succinate and malate that, in turn, activated hypoxia-inducible factor (HIF)-1α. Interestingly, the areas of stable HIF-1α expression overlapped with COX-2 and MMP-9 upregulation in LGs of DE-induced mice. We generated HIF-1α conditional knockout (CKO) mice in which HIF-1α expression was lost in the LG. Surprisingly, normal LG polarities and morphologies were completely lost with DE induction, and tremendous acinar cell apoptosis was observed. Similar to Sjögren's syndrome, CD3(+) and CD11b(+) cells infiltrated HIF-1α CKO LGs. Our results show that DE induced the expression of HIF-1α that activated autophagy signals to prevent further acinar cell damage and to maintain normal LG function.