title: Epidermal EGFR controls cutaneous host defense and prevents inflammation.
abstract: The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFR(Δep)) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.
authors: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Beate M
authors: BM
authors: Lichtenberger
authors: Peter A
authors: PA
authors: Gerber
authors: Martin
authors: M
authors: Holcmann
authors: Bettina A
authors: BA
authors: Buhren
authors: Nicole
authors: N
authors: Amberg
authors: Viktoria
authors: V
authors: Smolle
authors: Holger
authors: H
authors: Schrumpf
authors: Edwin
authors: E
authors: Boelke
authors: Parinaz
authors: P
authors: Ansari
authors: Colin
authors: C
authors: Mackenzie
authors: Andreas
authors: A
authors: Wollenberg
authors: Andreas
authors: A
authors: Kislat
authors: Jens W
authors: JW
authors: Fischer
authors: Katharina
authors: K
authors: Röck
authors: Jürgen
authors: J
authors: Harder
authors: Jens M
authors: JM
authors: Schröder
authors: Bernhard
authors: B
authors: Homey
authors: Maria
authors: M
authors: Sibilia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003872:Dermatitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D018859:Hair Follicle / Q000276:immunology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology; D007801:Langerhans Cells / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D011799:Quinazolines / Q000009:adverse effects; D012867:Skin / Q000187:drug effects / Q000276:immunology*; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors