New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of beta-defensins, LL37, and TLR2.
Epidermal keratinocytes differentiate and form a multilayered epidermis, which is the primary barrier between the body and the outer environment. As the epidermis is constantly exposed to a variety of microbial pathogens, its function of resisting microbial pathogens is vital. This characteristic feature is formed during differentiation. Immunohistochemical analysis revealed that the upper epidermis of normal human skin expresses beta-defensins 1-3 and LL37. We hypothesized that epidermal keratinocytes develop an innate immune barrier based on human beta-defensins (hBD) and LL37 during differentiation. To prove this, we introduced an active form of the apoptosis signal-regulating kinase-1 (ASK1), an intracellular regulator of keratinocyte differentiation, into cultured normal human keratinocytes. Transfection of this active form, ASK1-DeltaN, significantly enhanced the expression of hBD1-3 and LL37. In addition, a p38 inhibitor abolished this induction, indicating that the ASK1-p38 cascade regulates the expression of hBD1-3 and LL37. Furthermore, the ASK1-p38 pathway also regulated the expression of Toll-like receptor (TLR)2 in keratinocytes. Contact between S. aureus and keratinocytes resulted in the phosphorylation of p38 and induced the expression of hBD2 and hBD3. Moreover, the p38 inhibitor reduced this induction. In conclusion, the ASK1-p38 cascade regulates the innate immunity of the skin by forming an immune barrier consisting of hBD, LL37, and TLR2 during epidermal differentiation.
Sayama
Koji
K
Department of Dermatology, Ehime University School of Medicine, Ehime, Japan. sayama@m.ehime-u.ac.jp
Komatsuzawa
Hitoshi
H
Yamasaki
Kenshi
K
Shirakata
Yuji
Y
Hanakawa
Yasushi
Y
Ouhara
Kazuhisa
K
Tokumaru
Sho
S
Dai
Xiuju
X
Tohyama
Mikiko
M
Ten Dijke
Peter
P
Sugai
Motoyuki
M
Ichijo
Hidenori
H
Hashimoto
Koji
K
D023181:Antimicrobial Cationic Peptides / Q000032:analysis / Q000235:genetics*; D054804:Cathelicidins; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007113:Immunity, Innate; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology*; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics*; D012867:Skin / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D023083:beta-Defensins / Q000032:analysis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D007093:Imidazoles; D008562:Membrane Glycoproteins; D011725:Pyridines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D023083:beta-Defensins; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C093642:SB 203580