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

Abstract

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.

BLIMP1 Is Required for Postnatal Epidermal Homeostasis but Does Not Define a Sebaceous Gland Progenitor under Steady-State Conditions

“…Deletion of Blimp1 in the entire epidermis was confirmed as reported previously (Figure S2) (Chiang et al., 2013). Hematoxylin and eosin (H&E) staining of neck skin sections collected 2, 3, and 6 months after tamoxifen injection revealed clear differences between control and Blimp1 cKO epidermis, with epidermal loss of Blimp1 resulting in SG enlargement, IFE thickening, accumulation of cornified layers, and hyperkeratosis of the HF infundibulum (Figures 3C and 3D).…”

“…These changes are consistent with a defective epidermal barrier (Magnúsdóttir et al., 2007) and would explain the massive inflammatory infiltrate in the dermis (Figure 3D) (Chiang et al., 2013). Staining for the hair shaft marker K31 did not reveal any abnormalities in the lower, cycling portion of the HF (Figure 3P) (Horsley et al., 2006; Magnúsdóttir et al., 2007).…”

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

“…It is also a key player in epithelial cell differentiation (42,43). The 789-amino-acid BLIMP1 protein contains five zinc finger domains, the first two of which are critical for the ability of the protein to bind directly to DNA via sequences resembling the BLIMP1 consensus site, 5=-(A/C)AG(T/C)GAAAG(T/C)(G/T)-3= (see Fig.…”

Transcription Factor ABF-1 Suppresses Plasma Cell Differentiation but Facilitates Memory B Cell Formation

“…TG or WT mice were immunized i.p. with 100 mg (4-hydroxy-3-nitrophenyl) acetyl (NP) 25 -keyhole limpet hemocyanin (KLH) (Biosearch Technologies) in the primary and secondary immunizations (6 wk apart).…”

“…The following procedures and data analysis were performed essentially as previously described (25). The microarray dataset from this study is deposited at the National Center for Biotechnology Information Gene Expression Omnibus with accession number GSE26583 (http://www.ncbi.…”