SerpinB2 Deficiency Results in a Stratum Corneum Defect and Increased Sensitivity to Topically Applied Inflammatory Agents.
SerpinB2 (plasminogen activator inhibitor type 2) is constitutively expressed at high levels by differentiating keratinocytes in mice and humans; however, the physiological function of keratinocyte SerpinB2 remains unclear. Herein, we show that SerpinB2(-/-) mice are more susceptible to contact dermatitis after topical application of dinitrofluorobenzene, and show enhanced inflammatory lesions after topical applications of phorbol ester. Untreated SerpinB2(-/-) mice showed no overt changes in epithelial structure, and we were unable to find evidence for a role for keratinocyte SerpinB2 in regulating immunity, apoptosis, IL-1β production, proteasomal activity, or wound healing. Instead, the phenotype was associated with impaired skin barrier function and a defective stratum corneum, with SerpinB2(-/-) mice showing increased transepidermal water loss, increased overt loss of stratum corneum in inflammatory lesions, and impaired stratum corneum thickening after phorbol ester treatment. Immunoblotting suggested that SerpinB2 (cross-linked into the cornified envelope) is present in the stratum corneum and retains the ability to form covalent inhibitory complexes with urokinase. Data suggest that the function of keratinocyte SerpinB2 is protection of the stratum corneum from proteolysis via inhibition of urokinase, thereby maintaining the integrity and barrier function of the stratum corneum, particularly during times of skin inflammation. Implications for studies involving genetically modified mice treated with topical agents and human dermatological conditions, such as contact dermatitis, are discussed.
Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Wayne A
WA
Schroder
Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Itaru
I
Anraku
Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Thuy T
TT
Le
School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Thiago D C
TD
Hirata
School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Helder I
HI
Nakaya
Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Lee
L
Major
University of Queensland Diamantina Institute, Translation Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
Jonathan J
JJ
Ellis
Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Electronic address: andreas.suhrbier@qimrberghofer.edu.au.
Andreas
A
Suhrbier
D000818:Animals; D003877:Dermatitis, Contact / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017396:Plasminogen Activator Inhibitor 2 / Q000172:deficiency / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017396:Plasminogen Activator Inhibitor 2; D014568:Urokinase-Type Plasminogen Activator