Chymase Inhibitor Improves Dermatitis in NC/Nga Mice

Watanabe, Naohiro; Tomimori, Yoshiaki; Saito, Kieko; Miura, Kazuhiro; Wada, Adumi; Tsudzuki, Masaoki; Fukuda, Yoshiaki

doi:10.1159/000064256

Cited by 53 publications

(33 citation statements)

References 20 publications

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“…Injection of human chymase into mouse ear also resulted in polymorphonuclear cell recruitment (41,42). Moreover, a chymase inhibitor significantly impaired cell recruitment in several experimentally induced and natural dermatitis models, indicating that chymase plays a role in dermal inflammatory reactions (41)(42)(43)(44). These in vivo studies indicate that either chymase activates a resident, dormant chemokine, or that chymase itself is chemotactic.…”

Section: Discussionmentioning

confidence: 86%

Proteolytic Activation of Alternative CCR1 Ligands in Inflammation

Berahovich

Miao

Wang

et al. 2005

The Journal of Immunology

152

126

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Although chemokines CCL3/MIP-1α and CCL5/RANTES are considered to be primary CCR1 ligands in inflammatory responses, alternative CCR1 ligands have also been described. Indeed, four such chemokines, CCL6/C10/MIP-related protein-1, CCL9/MIP-1γ/MIP-related protein-2, CCL15/MIP-1δ/hemofiltrate CC chemokine-2/leukotactin-1, and CCL23/CKβ8/myeloid progenitor inhibitory factor-1, are unique in possessing a separately encoded N-terminal domain of 16–20 residues and two additional precisely positioned cysteines that form a third disulfide bridge. In vitro, these four chemokines are weak CCR1 agonists, but potency can be increased up to 1000-fold by engineered or expression-associated N-terminal truncations. We examined the ability of proinflammatory proteases, human cell supernatants, or physiological fluids to perform N-terminal truncations of these chemokines and thereby activate their functions. Remarkably, most of the proteases and fluids removed the N-terminal domains from all four chemokines, but were relatively unable to cleave the truncated forms further. The truncated chemokines exhibited up to 1000-fold increases in CCR1-mediated signaling and chemotaxis assays in vitro. In addition, N-terminally truncated CCL15/MIP-1δ and CCL23/CKβ8, but not CCL3/MIP-1α or CCL5/RANTES, were detected at relatively high levels in synovial fluids from rheumatoid arthritis patients. These data suggest that alternative CCR1 ligands are converted into potent chemoattractants by proteases released during inflammatory responses in vivo.

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Section: Discussionmentioning

confidence: 86%

Proteolytic Activation of Alternative CCR1 Ligands in Inflammation

Berahovich

Miao

Wang

et al. 2005

The Journal of Immunology

152

126

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“…Stimulation of high-affinity receptors for IgE on mast cells induces secretion of a variety of inflammatory mediators such as histamine, substance P and chymase [23, 24]. Based on the fact that these mediators induce itching and an intense desire to scratch [25], mast cells are thought to play a part in the pathogenesis of AD.…”

Section: Discussionmentioning

confidence: 99%

Dietary Pulverized Konjac Glucomannan Suppresses Scratching Behavior and Skin Inflammatory Immune Responses in NC/Nga Mice

Onishi

Kawamoto²,

Suzuki

et al. 2007

Int Arch Allergy Immunol

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Background: Feeding with pulverized konjac glucomannan (PKGM) suppresses the development of eczema and hyper-IgE production in NC/Nga mice, a model of atopic dermatitis. This study aimed to examine the effects of PKGM on scratching behavior and skin inflammatory immune responses in NC/Nga mice. Methods: Four-week-old NC/Nga mice were maintained for 8 or 9 weeks on diet containing PKGM. Scratching behavior and clinical symptoms were evaluated every 2 weeks. Effects of PKGM on cutaneous inflammation were evaluated by histopathological analysis. Local expression levels of substance P and proinflammatory cytokines were measured by ELISA. Results: An increase in scratching behavior was evident from 6 weeks of age in control mice, but this symptom was dose-dependently inhibited in PKGM-fed mice. Continuous PKGM feeding then significantly inhibited eczematous skin lesions including hyperkeratosis, dermal mastocytosis and eosinophilia. Concomitantly, cutaneous overproductions of substance P, IL-10, IL-4, and TNF-α were all suppressed in PKGM-fed mice. Conclusions: PKGM feeding markedly suppressed development of scratching behavior, substance P expression with mastocytosis, and skin inflammatory immune responses in NC/Nga mice.

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“…106 In addition, chymase inhibitors have anti-inflammatory functions, for example, by reducing the eosinophilia during N brasiliensis infection 107 and by preventing eosinophil accumulation in a model for atopic dermatitis. 108 Together, this development strongly implicates chymase as a promising therapeutic target in variety of clinical settings, and we anticipate that this notion will be evaluated through clinical trials in the near future. However, it is important to use MC protease inhibitors with caution because they may interfere with beneficial functions of MC proteases, for example, in connection with bacterial and parasite infection.…”

Section: Chymase Inhibitorsmentioning

confidence: 94%

Mast cell proteases: multifaceted regulators of inflammatory disease

Pejler

Rönnberg

Waern

et al. 2010

Blood

331

296

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IntroductionMast cells (MCs) are still mainly known for their harmful effects in connection with allergic reactions. However, this simplistic view is currently being extensively modified, and it is becoming more and more established that MCs have a complex array of functions and can contribute to a number of additional disorders. 1 In addition to being detrimental, MCs also carry out a number of beneficial functions, most notably in connection with innate immune responses toward various pathogens. 2 Moreover, recent studies indicate that MCs can play important roles in down-regulating adaptive immune responses. 3,4 As a consequence of this progress, MCs are gaining a massively increased interest worldwide, and much effort is invested into investigations of the mechanisms by which MCs contribute to different disorders.A striking morphologic feature of MCs is their abundance of electron-dense secretory granules, which contain large amounts of preformed compounds commonly referred to as "MC mediators." These include biogenic amines (histamine and serotonin), certain preformed cytokines (most notably tumor necrosis factor), serglycin proteoglycans, various lysosomal enzymes, and a number of MC-specific proteases of chymase, tryptase, or carboxypeptidase A (MC-CPA) type. [5][6][7][8] When MCs are induced to undergo degranulation, for example, through engagement of Fc⑀RI-bound IgE by polyvalent antigen, these mediators are thus released. 9 The MC proteases are expressed at exceptionally high levels, with mRNA levels approaching and even exceeding those of classic housekeeping genes, 10 and they are stored in remarkably high amounts. Indeed, it has been calculated that MC proteases may account for more than 25% of the total MC protein. 11,12 Importantly, in contrast to, for example, the pancreatic digestive proteases, the MC proteases are stored in fully active form; and when MCs undergo degranulation, large amounts of enzymatically active proteases are thus released into the extracellular space and probably have a profound impact on any condition in which MC degranulation occurs (Figure 1). Indeed, a plethora of potential functions of the MC proteases have previously been outlined, based on various approaches. 6 However, it is not until relatively recently that the in vivo functions of these enzymes have started to become unraveled through experimental approaches involving MC proteasedeficient mice. In this review, we summarize these findings and discuss their implications. Substrate specificity, distribution, and storageThe term "MC proteases" usually refers to the proteases that are expressed specifically by MCs and are stored in their secretory granules, that is, chymases, tryptases, and MC-CPA. However, it should be pointed out that MCs express a number of additional, non-MC-specific, proteases, such as lysosomal cathepsins, granzymes, neurolysin, and, possibly, cathepsin G. 6 Recently, the strictly MC-specific expression of the chymases has been used to generate mouse strains in which the Cre recombinase is expre...

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Chymase Inhibitor Improves Dermatitis in NC/Nga Mice

Cited by 53 publications

References 20 publications

Proteolytic Activation of Alternative CCR1 Ligands in Inflammation

Proteolytic Activation of Alternative CCR1 Ligands in Inflammation

Dietary Pulverized Konjac Glucomannan Suppresses Scratching Behavior and Skin Inflammatory Immune Responses in NC/Nga Mice

Mast cell proteases: multifaceted regulators of inflammatory disease

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