Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-04, Vol.110 (16), p.6476-6481
• Main Authors: Chiang, Ming-Feng, Yang, Shii-Yi, Lin, I-Ying, Hong, Jin-Bon, Lin, Sung-Jan, Ying, Hsia-Yuan, Chen, Chun-Ming, Wu, Shih-Ying, Liu, Fu-Tong, Lin, Kuo-I
• Format: Article
• Language: English
• Subjects: Animals; B lymphocytes; Biological Sciences; Cytokines; Cytokines - metabolism; Dermatitis - genetics; Dermatitis - physiopathology; Dinitrofluorobenzene; Eczema; Epidermis; Epidermis - metabolism; Flow Cytometry; Fluorescent Antibody Technique; Gene Deletion; Gene expression; Genes; Granulocyte Colony-Stimulating Factor - metabolism; Immunoblotting; Immunology; Inflammation; Keratinocytes; Keratinocytes - metabolism; Lymphocytes; Macrophages - immunology; Mice; Neutrophil Infiltration - immunology; Neutrophils; Positive Regulatory Domain I-Binding Factor 1; Proteins; Real-Time Polymerase Chain Reaction; Rodents; Skin; Skin diseases; T lymphocytes; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1219462110

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor important for the differentiation and function of several types of immune cells. Because skin serves as a physical barrier and acts as an immune sentinel, we investigated whether Blimp-1 is involved in epidermal immune function. We show that Blimp-1 expression is reduced in skin lesions of some human eczema samples and in stimulated primary keratinocytes. Epidermal-specific deletion of PR domain containing 1, with ZNF domain (Prdm1), the gene encoding Blimp-1, in adult mice caused spontaneously inflamed skin characterized by massive dermal infiltration of neutrophils/macrophages and development of chronic inflammation associated with higher levels of cytokines/chemokines, including granulocyte colony-stimulating factor (G-CSF), and enhanced myelopoiesis in bone marrow. Deletion of Prdm1 in the epidermis of adult mice also led to stronger inflammatory reactions in a tape-stripping test and in a disease model of contact dermatitis. The elevated G-CSF produced by keratinocytes after deletion of Prdm1 in vitro was mediated by the transcriptional activation of FBJ osteosarcoma oncogene (Fos) and fos-like antigen 1 (Fosl1). Systemic increases in G-CSF contributed to the inflammatory responses, because deletion of the G-CSF gene [colony stimulating factor 3, (Csf3)] prevented neutrophilia and partially ameliorated the inflamed skin in Prdm1- deficient mice. Our findings indicate a previously unreported function for Blimp-1 in restraining steady-state epidermal barrier immunity.