Crosstalk between keratinocytes and adaptive immune cells in an IkappaBalpha protein-mediated inflammatory disease of the skin.
Inflammatory diseases at epithelial borders develop from aberrant interactions between resident cells of the tissue and invading immunocytes. Here, we unraveled basic functions of epithelial cells and immune cells and the sequence of their interactions in an inflammatory skin disease. Ubiquitous deficiency of the IkappaBalpha protein (Ikba(Delta)(/Delta)) as well as concomitant deletion of Ikba specifically in keratinocytes and T cells (Ikba(K5Delta/K5Delta lckDelta/lckDelta)) resulted in an inflammatory skin phenotype that involved the epithelial compartment and depended on the presence of lymphocytes as well as tumor necrosis factor and lymphotoxin signaling. In contrast, mice with selective ablation of Ikba in keratinocytes or lymphocytes showed inflammation limited to the dermal compartment or a normal skin phenotype, respectively. Targeted deletion of RelA from epidermal keratinocytes completely rescued the inflammatory skin phenotype of Ikba(Delta)(/Delta) mice. This finding emphasizes the important role of aberrant NF-kappaB activation in both keratinocytes and lymphocytes in the development of the observed inflammatory skin changes.
Rebholz
Bernd
B
Department of Dermatology and Allergology, Ludwig-Maximilians-University Munich, Frauenlobstrasse 9-11, D-80337 Munich, Germany.
Haase
Ingo
I
Eckelt
Birgit
B
Paxian
Stephan
S
Flaig
Michael J
MJ
Ghoreschi
Kamran
K
Nedospasov
Sergei A
SA
Mailhammer
Reinhard
R
Debey-Pascher
Svenja
S
Schultze
Joachim L
JL
Weindl
Günther
G
Förster
Irmgard
I
Huss
Ralf
R
Stratis
Athanasios
A
Ruzicka
Thomas
T
Röcken
Martin
M
Pfeffer
Klaus
K
Schmid
Roland M
RM
Rupec
Rudolf A
RA
D000038:Abscess / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D002450:Cell Communication; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004817:Epidermis / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D007633:Keratins / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D000072000:NF-KappaB Inhibitor alpha; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020672:I-kappa B Proteins; D008233:Lymphotoxin-alpha; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D007633:Keratins