TY - JOUR
T1 - The epidermal growth factor receptor is a regulator of epidermal complement component expression and complement activation.
AU - Abu-Humaidan, Anas
AU - Ananthoju, Nageshwar
AU - Mohanty, Tirthankar
AU - Sonesson, Andreas
AU - Alberius, Per
AU - Schmidtchen, Artur
AU - Garred, Peter
AU - Sørensen, Ole E
PY - 2014
Y1 - 2014
N2 - The complement system is activated in response to tissue injury. During wound healing, complement activation seems beneficial in acute wounds but may be detrimental in chronic wounds. We found that the epidermal expression of many complement components was only increased to a minor extent in skin wounds in vivo and in cultured keratinocytes after exposure to supernatant from stimulated mononuclear cells. In contrast, the epidermal expression of complement components was downregulated in ex vivo injured skin lacking the stimulation from infiltrating inflammatory cells but with intact injury-induced epidermal growth factor receptor (EGFR)-mediated growth factor response. In cultured primary keratinocytes, stimulation with the potent EGFR ligand, TGF-α, yielded a significant downregulation of complement component expression. Indeed, EGFR inhibition significantly enhanced the induction of complement components in keratinocytes and epidermis following stimulation with proinflammatory cytokines. Importantly, EGFR inhibition of cultured keratinocytes either alone or in combination with proinflammatory stimulus promoted activation of the complement system after incubation with serum. In keratinocytes treated solely with the EGFR inhibitor, complement activation was dependent on serum-derived C1q, whereas in keratinocytes stimulated with a combination of proinflammatory cytokines and EGFR inhibition, complement activation was found even with C1q-depleted serum. In contrast to human keratinocytes, EGFR inhibition did not enhance complement component expression or cause complement activation in murine keratinocytes. These data demonstrate an important role for EGFR in regulating the expression of complement components and complement activation in human epidermis and keratinocytes and, to our knowledge, identify for the first time a pathway important for the epidermal regulation of complement activation.
AB - The complement system is activated in response to tissue injury. During wound healing, complement activation seems beneficial in acute wounds but may be detrimental in chronic wounds. We found that the epidermal expression of many complement components was only increased to a minor extent in skin wounds in vivo and in cultured keratinocytes after exposure to supernatant from stimulated mononuclear cells. In contrast, the epidermal expression of complement components was downregulated in ex vivo injured skin lacking the stimulation from infiltrating inflammatory cells but with intact injury-induced epidermal growth factor receptor (EGFR)-mediated growth factor response. In cultured primary keratinocytes, stimulation with the potent EGFR ligand, TGF-α, yielded a significant downregulation of complement component expression. Indeed, EGFR inhibition significantly enhanced the induction of complement components in keratinocytes and epidermis following stimulation with proinflammatory cytokines. Importantly, EGFR inhibition of cultured keratinocytes either alone or in combination with proinflammatory stimulus promoted activation of the complement system after incubation with serum. In keratinocytes treated solely with the EGFR inhibitor, complement activation was dependent on serum-derived C1q, whereas in keratinocytes stimulated with a combination of proinflammatory cytokines and EGFR inhibition, complement activation was found even with C1q-depleted serum. In contrast to human keratinocytes, EGFR inhibition did not enhance complement component expression or cause complement activation in murine keratinocytes. These data demonstrate an important role for EGFR in regulating the expression of complement components and complement activation in human epidermis and keratinocytes and, to our knowledge, identify for the first time a pathway important for the epidermal regulation of complement activation.
U2 - 10.4049/jimmunol.1302305
DO - 10.4049/jimmunol.1302305
M3 - Article
C2 - 24591374
SN - 1550-6606
VL - 192
SP - 3355
EP - 3364
JO - Journal of immunology
JF - Journal of immunology
IS - 7
ER -