Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation.
During inflammatory skin disorders such as psoriasis, atopic dermatitis, and allergic contact dermatitis, epidermal keratinocytes overexpress large amounts of soluble epidermal growth factor receptor ligands in response to tumor necrosis factor alpha and interferon gamma. These cytokines also promote de novo synthesis of numerous chemokines, including CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and CXCL8/IL-8, in turn responsible for the recruitment of different leukocyte populations. This study demonstrates that stimulation of EGFR down-regulates CCL2, CCL5, and CXCL10, while it increases CXCL8 expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, and reduced CXCL8 expression. In a mouse model of contact hypersensitivity, a single topical administration of a selective EGFR kinase blocker before antigen challenge results in a markedly enhanced immune response with increased chemokine expression and heavier inflammatory cell infiltrate. Targeting EGFR on epithelial cells may thus have profound impact on inflammatory and immune responses.
Mascia
Francesca
F
Laboratory of Immunology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carottere Scientifico, Rome, Italy.
Mariani
Valentina
V
Girolomoni
Giampiero
G
Pastore
Saveria
S
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D046508:Culture Techniques; D003877:Dermatitis, Contact / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D066246:ErbB Receptors