Processing of laminin α chains generates peptides involved in wound healing and host defense.
Laminins play a fundamental role in basement membrane architecture and function in human skin. The C-terminal laminin G domain-like (LG) modules of laminin α chains are modified by proteolysis to generate LG1-3 and secreted LG4-5 tandem modules. In this study, we provide evidence that skin-derived cells process and secrete biologically active peptides from the LG4-5 module of the laminin α3, α4 and α5 chain in vitro and in vivo. We show enhanced expression and processing of the LG4-5 module of laminin α3 in keratinocytes after infection and in chronic wounds in which the level of expression and further processing of the LG4-5 module correlated with the speed of wound healing. Furthermore, bacterial or host-derived proteases promote processing of laminin α3 LG4-5. On a functional level, we show that LG4-5-derived peptides play a role in wound healing. Moreover, we demonstrate that LG4-derived peptides from the α3, α4 and α5 chains have broad antimicrobial activity and possess strong chemotactic activity to mononuclear cells. Thus, the data strongly suggest a novel multifunctional role for laminin LG4-5-derived peptides in human skin and its involvement in physiological processes and pathological conditions such as inflammation, chronic wounds and skin infection.
Division of Dermatooncology, Center for Medical Research, University Medical Clinic, Tübingen, Germany.
Ilknur
I
Senyürek
Wolfgang E
WE
Kempf
Gerd
G
Klein
Andreas
A
Maurer
Hubert
H
Kalbacher
Luisa
L
Schäfer
Ines
I
Wanke
Christina
C
Christ
Stefan
S
Stevanovic
Martin
M
Schaller
Patricia
P
Rousselle
Claus
C
Garbe
Tilo
T
Biedermann
Birgit
B
Schittek
D000890:Anti-Infective Agents / Q000378:metabolism*; D001424:Bacterial Infections / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology*; D002461:Cell Line, Transformed; D002470:Cell Survival; D002633:Chemotaxis; D006801:Humans; D007113:Immunity, Innate; D015603:Keratinocytes / Q000382:microbiology / Q000502:physiology*; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012867:Skin / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D014945:Wound Healing
D000890:Anti-Infective Agents; D007797:Laminin; D010446:Peptide Fragments; C084098:laminin A