SerpinB2 Deficiency Results in a Stratum Corneum Defect and Increased Sensitivity to Topically Applied Inflammatory Agents

Abstract

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.

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

“…The reported role of SERPINB2 in regulation of Th1/Th2 balance is in line with our results demonstrating that reduced amount of SERPINB2 leads to increased production of IL‐8, CCL5 and CXCL5 by keratinocytes and increased migration of neutrophils. These results also are in line with a previous study demonstrating that SerpinB2 −/− mice are more susceptible to dinitrofluorobenzene‐induced contact dermatitis and indicate that SERPINB2 may also have anti‐inflammatory function in psoriasis. However, as SERPINB2 increased expression was found in psoriatic lesions, the anti‐inflammatory effect of SERPINB2 is not sufficient to eliminate inflammation in psoriatic skin.…”

“…Extracellular SERPINB2 is able to inhibit keratinocyte proliferation by inhibition of uPA, which has a growth stimulatory effect . One suggested role for SERPINB2 is the protection of the Stratum corneum in inflammatory conditions . The function in the protection of skin barrier is supported by SERPINB2 localization in the spinous layer and outwards in healthy epidermis .…”

Morpho‐regulation in diverse chicken feather formation: Integrating branching modules and sex hormone‐dependent morpho‐regulatory modules

“…The male LFS expressed CILP2, cartilage intermediate layer protein 2, may be associated with collagen VI which regulates fibroblast motility in the skin (Bernardo et al., ; Theocharidis et al., ). The female PE expressed COL8A1, collagen type VIII alpha 1 is an extracellular matrix molecule; FLT4, Fms related tyrosine kinase 4 is involved in lymphangiogenesis and angiogenesis; HGF/SF, Hepatocyte growth factor/Scatter factor has been reported to promote hair growth (Lindner et al., ; Qi et al., ); MMRN1, Multimerin 1 is found in platelets and the endothelium of blood vessels; TFPI2, Tissue factor pathway inhibitor 2 which is associated with melanoma when methylated (Lo Nigro et al., ); and TIE1, Tyrosine kinase with immunoglobulin like and EGF like domains 1 is a marker of endothelial cells (Talavera‐Adame et al., ); whereas the male PE epidermis expressed SERPINB2, Serpin family member 2 whose loss induced the impairment of skin barrier function and the formation of a defective stratum corneum (Schroder et al., ); and surprisingly, the AR. We expected AR expression levels to be raised in male feather tissues.…”

“…Aldosterone is associated with increased growth hormone levels in humans (Bielohuby et al, 2009). ATF over expression in mouse hair outer root sheath cells induced large, abnormal hair follicles (Wang et al, 2007); CSRNP1, Cysteine and serine rich nuclear protein 1 which may have tumor suppressor activity (Gingras, Pelletier, Boyd, & Ihle, 2007); MMP13, Matrix metalloproteinase 13, which is involved in embryonic development and tissue remodeling and has been implicated in scarless wound healing in nude mice (Gawronska-Kozak, 2011); SOCS3, the suppressor of cytokinase signaling which inhibits signaling through the JAK/STAT pathway blocks the formation of alopecia areata (Gao, Jin, & Wu, 2017); KRT20 immunostaining of sclerosing adnexal neoplasms was found to be a strong indicator of Desmoplastic trichoepithelioma (Evangelista & North, 2015) and SPRY3 Serpin family member 2 whose loss induced the impairment of skin barrier function and the formation of a defective stratum corneum (Schroder et al, 2016); and surprisingly, the AR. We expected AR expression levels to be raised in male feather tissues.…”

Tattoo removal with ingenol mebutate

“…A resolving mononuclear cell infiltrate could also be seen in the dermis (Figure 2B, N). By Day 7, the epithelium had fully reformed (slightly thickened26) and the eschar had darkened and crusted, with tattoo microspheres clearly located within the eschar (Figure 2C, eschar).…”