Chymase Participates in Chronic Dermatitis by Inducing Eosinophil Infiltration

Abstract

SUMMARY:An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) to a mouse ear caused a transient skin swelling, and the repetition of the challenge enlarged the contact dermatitis. The repeated challenge with DNFB also induced eosinophil infiltration on the application site. Administration of a chymase inhibitor significantly inhibited the ear swelling as well as eosinophil accumulation. An intradermal injection of human chymase to the mouse ear also elicited transient skin swelling and eosinophil infiltration, both of which were augmented in proportion to the number of injections. Human serum albumin and heat-inactivated chymase failed to induce such skin reactions, suggesting the participation of proteolytic activity of the enzyme. In addition, chymase stimulated eosinophil migration in vitro in a concentration-dependent manner. Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration. It is therefore possible that chymase plays a role in pathogenesis of chronic dermatitis such as atopic dermatitis. (Lab Invest 2002, 82:789 -794).A topic dermatitis (AD) is a chronic eczematous skin disorder characterized by dry and itchy skin. The patients with AD often have a family history of other allergic diseases including asthma and hay fever. Although AD is known to be a manifestation of immediate hypersensitivity mediated by IgE, delayed-type hypersensitivity is also involved in the skin reaction of the patients (Tanaka et al, 1994;Varela et al, 1999). Interestingly, in mice, repeated application of contact sensitizing agents, such as 2,4-dinitrofluorobenzene (DNFB) and trinitrochlorobenzene, develops an immediate-type reaction, in contrast to a single application that causes a typical delayed-type reaction (Kitagaki et al, 1995(Kitagaki et al, , 1997. Repeated elicitation with such agents not only increases the serum level of IgE but also induces Th2-type cytokine expression (Nagai et al, 1997b). In addition, mast cell accumulation occurs in the dermis because of the repeated challenge (Kitagaki et al, 1995), as is often observed in AD patients. Therefore, this animal model is thought to be valuable for studying human AD.Chymase is a chymotrypsin-like serine protease and is primarily stored in secretory granules of mast cells (Schwartz and Austen, 1980). Chymase cleaves a variety of physiological substances, including metalloproteases (Fang et al, 1997), procollagen (Kofford et al, 1997), precursor of interleukin 1␤ (IL-1␤) (Mizutani et al, 1991b), and membrane-associated stem cell factor (Longley et al, 1997), while its precise role is not clear. Human mast cells are classified into two types, MC TC and MC T , based on their composition of serine protease (Irani et al, 1986). MC TC contains both chymase and tryptase, while MC T expresses tryptase but not chymase. Because MC TC predominates in the skin (Irani et al, 1989), chymase has been implicated in the pathogenesis of skin disorders complic...

Proteolytic Activation of Alternative CCR1 Ligands in Inflammation

“…These in vivo studies indicate that either chymase activates a resident, dormant chemokine, or that chymase itself is chemotactic. Although chymase was not found to be chemotactic in our study, two groups reported that this enzyme was chemotactic for human leukocytes in vitro (41,42,45). However, enzymatic activity was required for chemoattraction in each of these studies, raising the possibility that the actual chemoattractant might have been a chymase-derived cleavage fragment of an inactive chemokine secreted by the cells.…”

“…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.…”

“…Injection of human chymase or tryptase into guinea pig skin or mouse peritoneal cavity resulted in substantial neutrophil and eosinophil recruitment within 3 h (39,40). 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).…”

Mouse Models for Atopic Dermatitis Developed in Japan

“…These lines of evidence suggested a new model system for antigen-induced dermatitis. Alternatively, dermatitis can also be induced in NC mice by a hapten, such as 2,4-dinitrofluorobenzene (DNFB) (Tomimori et al, 2002, Tomimori et al, 2005, trinitrochlorobenzene (TNCB) (Taniguchi et al, 2003), or FITC (Hvid et al, 2009). Using these induced dermatitis models in NC mice, extensive surveys for therapeutic agents, both chemicals and herbal medicine, have been performed (Kobayashi et al, 2003, Lee et al, 2007, Jiang et al, 2009, Joo et al, 2009, Lee et al, 2010, Sung et al, 2011a, Sung et al, 2011b, Wu et al, 2011.…”

Cloning and expression of human colon mast cell carboxypeptidase

“…These include induction of microvascular leakage in skin of guinea pig [26] , stimulation of inflammatory cell accumulation in peritoneum of mouse [27,28] and modulation of mast cell degranulation [29,30] , indicating that they may be key mediators of allergic inflammation and promising targets for diagnosis and therapeutic intervention [31][32][33][34][35] . However, little is known about the function of hMC-CP except for its ability to cleave angiotension I [13] .…”