ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α–Endoplasmic Reticulum Stress–Beclin1 Autophagy Regulatory Pathway

Deng, Jiehui; Bian, Xianli; Ma, Xiaochun; Li, Jiangxia; Long, Feng; Shan, Shan; Yuan, Qianqian; Qian, Xiaohong; Li, Yan; Gao, Fei; Gong, Yaoqin; Liu, Qiji

doi:10.4049/jimmunol.1602124

Cited by 28 publications

(38 citation statements)

References 57 publications

(61 reference statements)

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“…It has been previously reported that an up-regulation of ORMDL3 is required to promote autophagy in endothelial cells upon ox-LDL treatment [25]. Moreover, in heterologous expression systems, it has been shown that ORMDL3 expression modulates autophagic flux induced by mTOR1 inhibition [26]. Autophagy is a process induced by different pathways that determine cell fates in different ways.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model

Kiefer

Casas

García-López

et al. 2019

IJMS

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Increased orosomucoid-like 3 (ORMDL3) expression levels, due to single nucleotide polymorphisms (SNPs), have been associated with several inflammatory diseases, including asthma and inflammatory bowel diseases. ORMDL proteins inhibit serine palmitoyltransferase (SPT), the first rate-limiting enzyme in de novo sphingolipid synthesis and alter cellular calcium homeostasis. Both processes are essential for immune response. The present study addresses ORMDL3 protein involvement in macrophage physiology using an overexpressing knock-in mouse model. Ceramide content was notably different in the bone-marrow-derived macrophages (BMDM) from the transgenic mouse model compared with the wild type (WT) macrophages. Our data revealed an alteration of de novo production of sphinganine upon BMDM activation in the transgenic mouse. Gene-expression analysis showed that alteration in ORMDL3 expression levels did not affect activation or macrophage polarization. Nevertheless, we studied phagocytosis and autophagy—crucial processes that are dependent on lipid membrane composition. Phagocytosis in transgenic macrophages was not affected by ORMDL3 overexpression, but we did find a reduction in toll-like receptor 4 (TLR-4)-mediated autophagy. Both genetic and functional studies have pointed to autophagy as an essential pathway involved in inflammation. We believe that our work provides new insights into the functional link between ORMDL3 expression and inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model

Kiefer

Casas

García-López

et al. 2019

IJMS

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“…Accordingly, the serum levels of inflammatory cytokines and anti‐nuclear antibodies (ANA) are eliminated in mice with B cell‐specific ablation of autophagy (Cd19‐Cre Atg5(f/f)) . Orosomucoid‐like 3 (ORMDL3), which can potentially mediate autophagy via ATF 6‐Beclin1 pathway, was observed to be upregulated in SLE, facilitating the survival of splenic B cells by promoting autophagy and suppressing apoptosis .…”

Section: Adaptive Immunitymentioning

confidence: 99%

Autophagy and immunological aberrations in systemic lupus erythematosus

Zhou

Zhang

2019

Eur J Immunol

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease, in which immune defects can occur at multiple points of the cascading auto‐aggressive immune reactions, resulting in a striking heterogeneity of clinical presentations. The clinical manifestations of such autoimmune response can be severe: common manifestations symptoms include rash and renal inflammation progressing to kidney failure. Autophagy, the cellular “self‐digestion” process, is a key factor in the interplay between innate and adaptive immunity. Dysregulation of autophagy has been implicated in numerous autoimmune diseases. Several lines of evidence from genomic studies, cell culture systems, animal models, and human patients are emerging to support the role of autophagy in progression and pathogenesis of SLE. In this review, we summarize recent key findings on the aberrations of autophagy in SLE, with a special focus on how deregulated autophagy promotes autoimmunity and renal damage. We will also discuss how the observed findings may be translated into therapeutic settings.

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“…Further cellular and model animal studies indicate that autophagy is upregulated in. various immune cells in SLE, including B cells, T cells and macrophages [29,[31][32][33][34][35][36][37][38][39][40][41][42][43][44]. Activation of autophagy is observed in B cells, especially naïve B cells from both the lupus NZB/W mouse model and human patients [31].…”

mentioning

confidence: 99%

Podocytes and autophagy: a potential therapeutic target in lupus nephritis

2019

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Recent studies suggest that defects in macroautophagy/autophagy contribute to the pathogenesis of systemic lupus erythamatosus (SLE), especially in adaptive immunity. The occurrence and progression of lupus nephritis (LN) is the end result of complex interactions between regulation of immune responses and pathological process by renal resident cells, but there is still a lot of missing information for establishing the role of autophagy in the pathogenesis of LN, and as a therapy target. In our recent study, we observed that autophagy is activated in LN, especially in podocytes. Based on in vitro assays, many of the most important mediators of the diseasepatients' sera, patients' IgG and IFNA/IFN-αcan induce autophagy in both murine and human podocytes, by reactive oxygen species production or MTORC1 inhibition; autophagy activation negatively associates with podocyte injury. With regard to intervention, autophagy activators can protect against podocyte injury, whereas autophagy inhibitors aggravate injury. Taken together, our findings suggest that podocyte autophagy is involved in lupus renal protection and may be a therapeutic target. These data shed new light on the role of rapamycin and autophagy inducers in the treatment of SLE.

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ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α–Endoplasmic Reticulum Stress–Beclin1 Autophagy Regulatory Pathway

Cited by 28 publications

References 57 publications

Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model

Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model

Autophagy and immunological aberrations in systemic lupus erythematosus

Podocytes and autophagy: a potential therapeutic target in lupus nephritis

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