ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy–Dependent Pathway

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.

Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways

“…Previous studies reported that antigen-mediated activation could also change the expression levels of ORMDL3. Thus, triggering of FcεRI with multivalent antigen decreased the ORMDL3 levels in mast cells (29,62), whereas challenge with allergen increased the levels of ORMDL3 in mouse bronchial epithelial cells, bone marrow-derived eosinophils, or lung macrophages (16).…”

“…The function of mast cells was recently examined in mice with locally silenced ORMDL3 ( 29 , 62 ) or in mice deficient in ORMDL2, ORMDL3, or both proteins ( 30 ). Passive cutaneous anaphylaxis was enhanced in mice with intradermally silenced ORMDL3 ( 29 , 62 ) or in double-deficient ORMDL2 and ORMDL3 KO mice ( 30 ).…”

“…The function of mast cells was recently examined in mice with locally silenced ORMDL3 ( 29 , 62 ) or in mice deficient in ORMDL2, ORMDL3, or both proteins ( 30 ). Passive cutaneous anaphylaxis was enhanced in mice with intradermally silenced ORMDL3 ( 29 , 62 ) or in double-deficient ORMDL2 and ORMDL3 KO mice ( 30 ). We assume that the increased passive cutaneous anaphylaxis in such mice is a result of increased mast cell responsiveness to which metabolites of sphingolipid and eicosanoid pathways are contributors ( 59 , 63 ).…”

“…Previous studies reported that antigen-mediated activation could also change the expression levels of ORMDL3. Thus, triggering of FcεRI with multivalent antigen decreased the ORMDL3 levels in mast cells ( 29 , 62 ), whereas challenge with allergen increased the levels of ORMDL3 in mouse bronchial epithelial cells, bone marrow-derived eosinophils, or lung macrophages ( 16 ). Treatment of macrophage cell line RAW267.4 or bone marrow-derived macrophages with lipopolysaccharide for 4 h decreased ORMDL expression, whereas sphinganine production was increased ( 12 , 66 ).…”

Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma

“… Turan et al (2019) proved through experiments that iDCs infected with TSV-1 could induce autophagy. Li et al (2021c) demonstrated that autophagy of mast cells could serve as a therapeutic target for allergic reactions. Ding et al (2021) revealed that neutrophils were associated with autophagy.…”