The Epidermal Growth Factor Receptor Is a Regulator of Epidermal Complement Component Expression and Complement Activation
Authors
Anas H. A. Abu-Humaidan, Nageshwar Ananthoju, Tirthankar Mohanty, Andreas Sonesson, Per Alberius, Artur Schmidtchen, Peter Garred, and Ole E. Sørensen
Institution
Lund University
Country
Sweden
Year
2014
Journal
J Immunology
Abstract
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-a, 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.