C10orf99/GPR15L Regulates Proinflammatory Response of Keratinocytes and Barrier Formation of the Skin

皮膚表面で産生されるペプチドのはたらきを発見 --アトピー性皮膚炎、乾癬でも--. 京都大学プレスリリース. 2022-02-22.The epidermis, outermost layer of the skin, forms a barrier and is involved in innate and adaptive immunity in an organism. Keratinocytes participate in all these three protective processes. However, a regulator of keratinocyte protective responses against external dangers and stresses remains elusive. We found that upregulation of the orphan gene 2610528A11Rik was a common factor in the skin of mice with several types of inflammation. In the human epidermis, peptide expression of G protein-coupled receptor 15 ligand (GPR15L), encoded by the human ortholog C10orf99, was highly induced in the lesional skin of patients with atopic dermatitis or psoriasis. C10orf99 gene transfection into normal human epidermal keratinocytes (NHEKs) induced the expression of inflammatory mediators and reduced the expression of barrier-related genes. Gene ontology analyses showed its association with translation, mitogen-activated protein kinase (MAPK), mitochondria, and lipid metabolism. Treatment with GPR15L reduced the expression levels of filaggrin and loricrin in human keratinocyte 3D cultures. Instead, their expression levels in mouse primary cultured keratinocytes did not show significant differences between the wild-type and 2610528A11Rik deficient keratinocytes. Lipopolysaccharide-induced expression of Il1b and Il6 was less in 2610528A11Rik deficient mouse keratinocytes than in wild-type, and imiquimod-induced psoriatic dermatitis was blunted in 2610528A11Rik deficient mice. Furthermore, repetitive subcutaneous injection of GPR15L in mouse ears induced skin inflammation in a dose-dependent manner. These results suggest that C10orf99/GPR15L is a primary inducible regulator that reduces the barrier formation and induces the inflammatory response of keratinocytes

Eremophilanes from Ligularia hookeri Collected in China and Structural Revision of 3β-Acyloxyfuranoeremophilan-15,6-olide

Chemical constituents of Ligularia hookeri (Asteraceae) collected in Yunnan and Sichuan Provinces in China were examined for the first time. Seven furanoeremophilanes, five of which were new, as well as known bisabolane- and eudesmane-type sesquiterpenoids, were isolated. Spectroscopic evidence indicates that the previously reported 3β-(2′-methylpropenoyloxy)furanoeremophilan-15,6β-olide should be revised to 3β-(2′-methylpropenoyloxy)furanoeremophilan-15,6α-olide