Allergic asthma is characterized by airway hyperreactivity, mucus hypersecretion, eosinophilic infiltration, and elevated serum IgE levels . Although the early proposed role of abnormal airway smooth muscles has not been clearly defined, infiltration of inflammatory cells such as eosinophils, macrophages, and lymphocytes in the airways of patients with asthma and the efficacy of corticosteroids in the majority of patients indicate that asthma is a chronic airway inflammatory disease . T cells play an important role during asthma pathogenesis, and T helper type 2 (Th2) cell differentiation is important in initiating and perpetuating events in asthma, particularly in experimental models [1, 2]. The role of innate inflammatory cells, such as mast cells, basophils, and recently defined innate lymphoid cells, has been suggested to provide a local cytokine environment that induces Th2 differentiation . In addition, epithelial cells at the mucosal surfaces have been accepted as integral components of innate and adaptive immunity [4, 5]. The important role of pulmonary epithelial cells during lung infection has been documented [5–7], and the critical role of epithelial cells in inflammatory amplification following non-infectious damage has recently been reported by our group .
Transglutaminase 2 (TG2) is a post-translational protein-modifying enzyme that catalyzes the transamidation reaction, producing crosslinked or polyaminated proteins. TG2 is expressed ubiquitously in various cellular compartments and participates in many biological processes, including extracellular matrix formation, wound healing, apoptosis, and differentiation [9, 10]. TG2 has also been implicated in many disease processes. Increased TG2 expression and activity have been reported in various inflammatory conditions, such as rheumatoid arthritis, gouty arthritis, and organ fibrosis [11–13]. Altered forms of proteins modified by TG2 enzymatic activity have been suggested in the pathogenesis of various diseases, such as celiac disease, cataracts, and Huntington’s disease [9, 10, 14–16]. Controversies exist regarding the pathological and protective roles of TG2 during inflammation, TG2 sustains inflammation through the release of inflammatory cytokines while minimizing inflammation by increasing the clearance of apoptotic cells [12, 17]. Recent disease animal models using TG2-deficient mice have revealed the important role of TG2 during the pathogenesis of bacterial sepsis, inflammation-associated pulmonary fibrosis, and autoimmune encephalitis [8, 18, 19]. TG2 is important during the initial inflammatory response. Specifically, TG2 induces nuclear factor-κB-dependent interleukin (IL)-6 secretion from lung epithelial cells, leading to Th17 differentiation in the lung . Epithelial cell-derived signaling mediators, such as IL-33, thymic stromal lymphopoietin (TSLP), and IL-25, initiate Th2 immune responses and each can direct the Th2 response either alone or through downstream mediators . Among these, IL-33 has been implicated as the most upstream mediator of epithelial cytokines . Since epithelial TG2 can initiate the inflammatory response of non-infectious tissue damage , we assumed the TG2 may also play an important role in initiating and perpetuating the epithelial inflammatory response leading to Th2 differentiation.
In this study, we investigated the role of TG2 in the pathogenesis of allergic asthma, particularly whether TG2 affects initial activation signaling by inducing IL-33 and downstream molecules leading to Th2 differentiation against antigens. Allergic asthma was induced by ovalbumin (OVA) sensitization and intranasal challenge. We found that airway hypersensitivity was attenuated in TG2-deficient mice compared to that in wild-type (WT) controls and recruitment of eosinophils and Th2 and Th17 differentiation was decreased in TG2-deficient mice. Treatment with cysteamine, a transglutaminase inhibitor, also reduced airway hypersensitivity, inflammatory cell recruitment, and T helper cell differentiation. TG2-deficient mice revealed decreased IL-33 expression following the induction of allergic asthma compared to that in the WT control. Thus, we provide evidence that TG2 in pulmonary epithelial cells initiates allergic responses by inducing the IL-33-Th2 signaling pathways.