Skin-Derived SPINK9 Kills Escherichia coli.

Antimicrobial peptides play a critical role in the barrier function of human skin. They offer a fast response to invading microorganisms and protect from external microbial infection. Here we show the isolation of the kallikrein-related peptidase inhibitor SPINK9 as a major antibacterial factor from healthy stratum corneum.

The serine protease inhibitor of Kazal-type 7 (SPINK7) is expressed in human skin.

Proteases and their inhibitors play an important role in epidermal homeostasis. Their imbalance contributes to severe skin diseases. SPINK7 is a member of the SPINK protease inhibitor family and has been described so far as a cancer-related gene in the esophagus.

Gingipains of Porphyromonas gingivalis Affect the Stability and Function of Serine Protease Inhibitor of Kazal-type 6 (SPINK6), a Tissue Inhibitor of Human Kallikreins.

Periodontitis, a chronic inflammation driven by dysbiotic subgingival bacterial flora, is linked on clinical levels to the development of a number of systemic diseases and to the development of oral and gastric tract tumors. A key pathogen, Porphyromonas gingivalis, secretes gingipains, cysteine proteases implicated as the main factors in the development of periodontitis. Here we hypothesize that gingipains may be linked to systemic pathologies through the deregulation of kallikrein-like proteinase (KLK) family members.

The solution structure of the kallikrein-related peptidases inhibitor SPINK6.

Kallikrein-related peptidases (KLKs) are crucial for epidermal barrier function and are involved in the proteolytic regulation of the desquamation process. Elevated KLK levels were reported in atopic dermatitis. In skin, the proteolytic activity of KLKs is regulated by specific inhibitors of the serine protease inhibitor of Kazal-type (SPINK) family.

The serine protease inhibitor of Kazal-type 9 (SPINK9) is expressed in lichen simplex chronicus, actinic keratosis and squamous cell carcinoma.

The serine protease inhibitor of Kazal-type (SPINK) 9 was reported to be exclusively expressed in palmoplantar skin. SPINK9 is a specific inhibitor of the serine protease kallikrein-related peptidase 5 (KLK5), which contributes to the desquamation process of the stratum corneum. Herein, we demonstrated that SPINK9 is also expressed in lichen simplex chronicus.

Kallikreins - The melting pot of activity and function.

The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Because of the broad spectrum of processes that are modulated by kallikreins, these proteases are the subject of extensive investigations. This review brings together basic information about the biochemical properties affecting enzymatic activity, with highlights on post-translational modifications, especially glycosylation.

Decreased susceptibility of Staphylococcus aureus small-colony variants toward human antimicrobial peptides.

Staphylococcus aureus is a frequent resident of human nose and skin in many individuals, but it is also able to cause a variety of serious infections including those of the skin and soft tissue. There is increasing evidence that particularly persistent, relapsing, and difficult-to-treat infections caused by S. aureus are associated with the formation of the small-colony variant (SCV) phenotype.

SPINK9 stimulates metalloprotease/EGFR-dependent keratinocyte migration via purinergic receptor activation.

Serine protease inhibitors of the Kazal-type 9 (SPINK9) is a keratinocyte-derived cationic peptide that is found most abundantly in the upper layers of the palmar-plantar epidermis. In vitro, the peptide displays the capacity to inhibit specifically kallikrein-related peptidase 5 (KLK5). Here, we report that cells expressing SPINK9 secrete the peptide constitutively.

Characterization of Spink6 in mouse skin: the conserved inhibitor of kallikrein-related peptidases is reduced by barrier injury.

The proteolytic regulation of the desquamation process by kallikrein-related peptidases (KLKs) is crucial for epidermal barrier function, and elevated KLK levels have been reported in atopic dermatitis. KLKs are controlled by specific inhibitors of the serine protease inhibitor of Kazal-type (Spink) family. Recently, SPINK6 was shown to be present in human stratum corneum.

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis.

Virulence factor secretion and assembly occurs at spatially restricted foci in some Gram-positive bacteria. Given the essentiality of the general secretion pathway in bacteria and the contribution of virulence factors to disease progression, the foci that coordinate these processes are attractive antimicrobial targets. In this study, we show in Enterococcus faecalis that SecA and Sortase A, required for the attachment of virulence factors to the cell wall, localize to discrete domains near the septum or nascent septal site as the bacteria proceed through the cell cycle.

Immunomodulatory effects of vitamin D on innate and adaptive immune responses to Streptococcus pneumoniae.

Background: Streptococcus pneumoniae forms part of the normal nasopharyngeal flora but can also cause a broad spectrum of inflammatory diseases. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides and suppression of T-cell proliferation, but its ability to modulate the immune response to pneumococci is unknown.

Methods: Monocyte-derived dendritic cells (DCs) were stimulated with pneumococcal peptidoglycan (PGN) in the presence or absence of vitamin D.

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency.

Differential expression and in vivo secretion of the antimicrobial peptides psoriasin (S100A7), RNase 7, human beta-defensin-2 and -3 in healthy human skin.

Antimicrobial peptides (AMP) are key players in the skin's defense system. Previous observations suggest a site- and age-dependent expression of individual AMP. We investigated the expression and secretion patterns of four important AMP in a representative collective of healthy human skin samples.

Staphylococcus aureus subverts cutaneous defense by D-alanylation of teichoic acids.

The Gram-positive bacterium Staphylococcus aureus is a frequent skin colonizer that often causes severe skin infections. It has been reported that neutralizing the negatively charged bacterial surface through the incorporation of d-alanine in its teichoic acids confers reduced susceptibility of S. aureus towards cationic antimicrobial peptides (AMPs).

Cross-linking of SPINK6 by transglutaminases protects from epidermal proteases.

Extracellular kallikrein-related peptidases (KLKs) are involved in the desquamation process and the initiation of epidermal inflammation by different mechanisms. Their action is tightly controlled by specific protease inhibitors. Recently, we have identified the serine protease inhibitor of Kazal-type (SPINK) 6 as a selective inhibitor of KLKs in human stratum corneum extracts.

Susceptibility of Staphylococcus aureus bacteremia strains to different skin-derived antimicrobial proteins.

Staphylococcus aureus is a major human pathogen causing cutaneous infections to life-threatening bacteremia. These infections are often caused by strains derived from the own microflora suggesting that a disturbed epidermal barrier may promote invasion of S. aureus.

Pseudomonas aeruginosa-derived rhamnolipids subvert the host innate immune response through manipulation of the human beta-defensin-2 expression.

Pseudomonas aeruginosa is a well-known cause of infections especially in compromised patients. To neutralize this pathogen, the expression of antimicrobial factors in epithelial cells is crucial. In particular the human beta-defensin hBD-2 is especially active against P.

Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice.

Objective: Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation.

Murine filaggrin-2 is involved in epithelial barrier function and down-regulated in metabolically induced skin barrier dysfunction.

The S100 fused-type proteins (SFTPs) are thought to be involved in the barrier formation and function of the skin. Mutations in the profilaggrin gene, one of the best investigated members of this family, are known to be the major risk factors for ichthyosis vulgaris and atopic dermatitis. Recently, we identified human filaggrin-2 as a new member of the SFTP family.

Epidermal proteases in the pathogenesis of rosacea.

A number of different proteases and their inhibitors have a role in skin physiology and in the pathophysiology of inflammatory skin diseases. Proteases are important in the desquamation process and orderly regulation of the skin's barrier function. On the basis of the catalytic domain, proteases are classified into aspartate-, cysteine-, glutamate-, metallo-, serine-, and threonine proteases.

Expression and regulation of murine SPINK12, a potential orthologue of human LEKTI2.

A balanced proteolytic activity in the epidermis is vital to maintain epidermal homoeostasis and barrier function. Distinct protease-inhibitor systems are operating in different epidermal layers. In the uppermost layer, the stratum corneum, kallikrein-like proteases and their inhibitors are responsible for desquamation of the cornified keratinocytes, thus regulating the integrity of the epidermal barrier.