Abstract
Orosomucoid like 3 (ORMDL3) encodes an ER-resident transmembrane protein that regulates the activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme for sphingolipid biosynthesis in cells. A decade ago, several genome wide association studies revealed single nucleotide polymorphisms associated with increased ORMDL3 protein expression and susceptibility to allergic asthma. Since that time, numerous studies have investigated how altered ORMDL3 expression might predispose to asthma and other autoimmune/inflammatory diseases. In this brief review, we focus on growing evidence suggesting that heightened ORMDL3 expression specifically in CD4+ T lymphocytes, the central orchestrators of adaptive immunity, constitutes a major underlying mechanism of asthma pathogenesis by skewing their differentiation and function. Furthermore, we explore how sphingolipid modulation in T cells might be responsible for these effects, and how further studies may interrogate this intriguing hypothesis.
Highlights
Asthma is a chronic lung disease associated with narrowing of airways, bronchial hyperreactivity, and increased mucus production
We might hypothesize that in patients carrying 17q12–21 asthma risk SNPs, dynamic changes in the expression and action of key endoplasmic reticulum (ER) SERCA pumps in response to T cell receptor (TCR) activation would be hindered by higher Orosomucoid like 3 (ORMDL3) expression in CD4+ T cells
Reduced interleukin-2 from T cells (IL-2) production and fate skewing, as noted in human T cells homozygous for 17q12–21 asthma risk SNPs and elevated ORMDL3 expression, may result from reductions in sphingolipid generation that hinder the shift to anabolic metabolism and macromolecule biosynthesis required during clonal T cell expansion and Th1 effector differentiation [49]
Summary
Asthma is a chronic lung disease associated with narrowing of airways, bronchial hyperreactivity, and increased mucus production. By re-examining previous studies in immune and non-immune cells from humans, mouse models and even lower organisms (e.g. yeast), we attempt to elucidate potential mechanisms by which ORMDL3 overexpression in CD4+ T cells may connect to enhanced pathophysiology of asthma in patients carrying the 17q12-21 risk SNPs. ORMDL3, SPT, AND SPHINGOLIPID REGULATION
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