Abstract
Treatment of cancer patients with epidermal growth factor receptor (EGFR) inhibitors causes perifollicular inflammation in the skin. Mouse models with EGFR deficiency predicted this folliculitis and revealed that abrogation of EGFR disrupts hair follicle cycling. Hair follicles transition between the anagen growth phase, a transitional catagen phase, and the dormant phase of telogen throughout life. We hypothesized that the defect in progression through catagen resulting from EGFR deficiency causes cutaneous inflammation. EGFR regulation of the hair cycle and inflammation was investigated using a skin-targeted deletion of Egfr (Krt14-Cre+/Egfrfl/fl mice). Dorsal hair follicles of control mice synchronously entered catagen at P17. In contrast, Egfr mutant follicles asynchronously entered catagen after P18 with some follicles remaining in aberrant anagen through P28. Mast cells were examined because follicular mast cell precursors can facilitate the transition into catagen after their maturation and degranulation. Failed catagen progression preceded an inflammatory response in the mutant skin, which was characterized by an increase in mast cell numbers beginning at P21. Neutrophils and macrophages increased in mutant skin by P28. Transcriptional profiling using follicular RNA was performed at normal catagen onset to identify EGFR-regulated mediators of the inflammatory response. In silico analyses of these data identified increased expression of 12 immune function genes in mutant hair follicles including the mast cell proteases Chymase and Tryptase and class I and II MHC molecules, consistent with a role for both innate and adaptive immunity in cutaneous inflammation following asynchronous catagen. The mitotic regulators Rcc2 and Sfi1 were increased correlating with our observation of G2-M accumulation in controls prior to catagen and sustained proliferation in mutants. Sixteen hair keratins and keratin-associated protein genes were decreased in mutants, which was associated with wavy hair and follicular abnormalities. Because chemotherapeutics like cyclophosphamide induce dystrophic catagen and alopecia, we hypothesized Egfr mutants would be resistant to alopecia. Mutants arrested in early catagen following cyclophosphamide, sustained less apoptosis, had less p53, and did not undergo alopecia in contrast to cyclophosphamide-treated controls. These results document pleiotropic roles for EGFR in follicular hair cycling, proliferation, differentiation and suppression of inflammation.