Abstract
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.
Highlights
Expression of the orosomucoid-like 3 (ORMDL3) gene has been genetically linked to pro-inflammatory diseases, such as asthma, Crohn’s disease, ulcerative colitis, and rheumatoid arthritis [1,2,3,4], suggesting ORMDL3 involvement in immune system function
We focus on macrophage physiology, paying special attention to ceramide synthesis and the processes derived from it, including activation, polarization, phagocytosis, and autophagy
We have previously described how macrophage activation underlies the coordinated regulation of all three ORMDL isoforms in order to allow the induction of de novo sphingolipid synthesis [12], which is linked to important processes in macrophage physiology, such as autophagy and phagocytosis [12]
Summary
Expression of the orosomucoid-like 3 (ORMDL3) gene has been genetically linked to pro-inflammatory diseases, such as asthma, Crohn’s disease, ulcerative colitis, and rheumatoid arthritis [1,2,3,4], suggesting ORMDL3 involvement in immune system function. This connection has led to extensive studies seeking to identify possible underlying mechanisms. We have previously described how macrophage activation underlies the coordinated regulation of all three ORMDL isoforms in order to allow the induction of de novo sphingolipid synthesis [12], which is linked to important processes in macrophage physiology, such as autophagy and phagocytosis [12]. Our results demonstrate the consequences of anomalous expression of ORMDL3 on ceramide homeostasis in macrophages, which affects important processes in innate immunity, such as autophagy
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