Abstract
Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy. Although ERS/UPR/autophagy pathway is crucial in Ag-induced mast cell activation, it is unknown whether ORMDL3 regulates the ERS/UPR/autophagy pathway during mast cell activation. In this study, we found that ORMDL3 expression was downregulated in Ag-activated MC/9 cells. Overexpression of ORMDL3 significantly inhibited degranulation, and cytokine/chemokine production, while the opposite effect was observed with ORMDL3 knockdown in MC/9 cells. Importantly, ORMDL3 overexpression upregulated mediators of ERS-UPR (SERCA2b, ATF6) and autophagy (Beclin 1 and LC3BII). Knockdown of ATF6 and/or inhibition of autophagy reversed the decreased degranulation and cytokine/chemokine expression caused by ORMDL3 overexpression. Moreover, in vivo knockdown of ORMDL3 and/or ATF6 enhanced passive cutaneous anaphylaxis (PCA) reactions in mouse ears. These data indicate that ORMDL3 suppresses Ag-mediated mast cell activation via an ATF6 UPR-autophagy dependent pathway and thus, attenuates anaphylactic reaction. This highlights a potential mechanism to intervene in mast cell mediated diseases.
Highlights
Mast cells are the key effector cells inducing immunoglobulin E (IgE)-mediated inflammatory responses to allergens in sensitized individuals [1]
This data confirms that Ag-activation downregulates ORMDL3 expression
Knockdown of activating transcription factor 6 (ATF6) and/or autophagy inhibition repressed ORMDL3-mediated inhibition of mast cell activation. This was nicely corroborated with the findings that ORMDL3-ATF6-unfolded protein response (UPR) suppressed passive cutaneous anaphylaxis (PCA) reaction. Taken together these data suggest that ORMDL3 negatively regulates mast cell activation and subsequent immune responses via ATF6autophagy dependent pathway (Figure 7)
Summary
Mast cells are the key effector cells inducing immunoglobulin E (IgE)-mediated inflammatory responses to allergens in sensitized individuals [1]. Upon subsequent exposure to the specific antigen, these sensitized mast cells undergo degranulation and release histamine and lipid mediators (prostaglandins, leukotrienes) followed by a diverse range of cytokines and chemokines [2]. These inflammatory mediators trigger acute allergic reactions as observed in allergic disorders, such as allergic asthma, atopic dermatitis, allergic rhinitis, and life-threatening anaphylaxis [3]. ORMDL3 binds to and inhibits the sarcoendoplasmic reticulum calcium ATPase (SERCA) 2b resulting in reduction of ER Ca2+ concentration and activation of ERS-induced UPR signaling in HEK293 cells [12, 22]. ORMDL3 has been shown to increase ATF6a level and subsequent induction of SERCA2b expression in human bronchial epithelial cells (BEC) [8], suggesting ORMDL3 mediated ERS-UPR response is cell-specific
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