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The epidermal growth factor receptor is a regulator of epidermal complement component expression and complement activation.

Abu-Humaidan, Anas LU ; Ananthoju, Nageshwar LU ; Mohanty, Tirthankar LU ; Sonesson, Andreas LU ; Alberius, Per LU ; Schmidtchen, Artur LU ; Garred, Peter and Sørensen, Ole E LU (2014) In Journal of immunology (Baltimore, Md. : 1950) 192(7). p.3355-3364
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of immunology (Baltimore, Md. : 1950)
volume
192
issue
7
pages
3355 - 3364
publisher
American Association of Immunologists
external identifiers
  • PMID:24591374
  • WOS:000333342800044
  • Scopus:84897474673
ISSN
1550-6606
DOI
10.4049/jimmunol.1302305
language
English
LU publication?
yes
id
4a01ca84-5287-4849-a6f9-97c4f5127f79 (old id 4383965)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24591374?dopt=Abstract
date added to LUP
2014-04-02 18:00:46
date last changed
2016-11-01 10:16:40
@misc{4a01ca84-5287-4849-a6f9-97c4f5127f79,
  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-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.},
  author       = {Abu-Humaidan, Anas and Ananthoju, Nageshwar and Mohanty, Tirthankar and Sonesson, Andreas and Alberius, Per and Schmidtchen, Artur and Garred, Peter and Sørensen, Ole E},
  issn         = {1550-6606},
  language     = {eng},
  number       = {7},
  pages        = {3355--3364},
  publisher    = {ARRAY(0x8a59cb0)},
  series       = {Journal of immunology (Baltimore, Md. : 1950)},
  title        = {The epidermal growth factor receptor is a regulator of epidermal complement component expression and complement activation.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1302305},
  volume       = {192},
  year         = {2014},
}