title: S100A8-S100A9 protein complex mediates psoriasis by regulating the expression of complement factor C3.
abstract: Psoriasis is a common heterogeneous inflammatory skin disease with a complex pathophysiology and limited treatment options. Here we performed proteomic analyses of human psoriatic epidermis and found S100A8-S100A9, also called calprotectin, as the most upregulated proteins, followed by the complement component C3. Both S100A8-S100A9 and C3 are specifically expressed in lesional psoriatic skin. S100A9 is shown here to function as a chromatin component modulating C3 expression in mouse and human cells by binding to a region upstream of the C3 start site. When S100A9 was genetically deleted in mouse models of skin inflammation, the psoriasis-like skin disease and inflammation were strongly attenuated, with a mild immune infiltrate and decreased amounts of C3. In addition, inhibition of C3 in the mouse model strongly reduced the inflammatory skin disease. Thus, S100A8-S100A9 can regulate C3 at the nuclear level and present potential new therapeutic targets for psoriasis.
authors: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Helia B
authors: HB
authors: Schonthaler
authors: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Juan
authors: J
authors: Guinea-Viniegra
authors: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Stefanie K
authors: SK
authors: Wculek
authors: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Isabel
authors: I
authors: Ruppen
authors: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Pilar
authors: P
authors: Ximénez-Embún
authors: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Ana
authors: A
authors: Guío-Carrión
authors: Department of Dermatology, Hospital Universitario La Princesa, 28006 Madrid, Spain.
authors: Raquel
authors: R
authors: Navarro
authors: Leukocyte Adhesion Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors: Nancy
authors: N
authors: Hogg
authors: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain.
authors: Keith
authors: K
authors: Ashman
authors: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 29029 Madrid, Spain. Electronic address: ewagner@cnio.es.
authors: Erwin F
authors: EF
authors: Wagner
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003176:Complement C3 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020543:Proteome; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D003176:Complement C3; D020543:Proteome; D034741:RNA, Small Interfering