biostudies-literatureJames BNNational Institute of Allergy and Infectious DiseasesIntramural NIH HHSNIAID NIH HHSNHLBI NIH HHSNational Cancer InstituteNCI NIH HHSNIGMS NIH HHSe22799https://www.ebi.ac.uk/biostudies/studies/S-EPMC9990076biostudies-literatureUnknown37(3)Genome-wide association studies have linked the ORM (yeast)-like protein isoform 3 (ORMDL3) to asthma severity. Although ORMDL3 is a member of a family that negatively regulates serine palmitoyltransferase (SPT) and thus biosynthesis of sphingolipids, it is still unclear whether ORMDL3 and altered sphingolipid synthesis are causally related to non-Th2 severe asthma associated with a predominant neutrophil inflammation and high interleukin-17 (IL-17) levels. Here, we examined the effects of ORMDL3 overexpression in a preclinical mouse model of allergic lung inflammation that is predominantly neutrophilic and recapitulates many of the clinical features of severe human asthma. ORMDL3 overexpression reduced lung and circulating levels of dihydrosphingosine, the product of SPT. However, the mosFASEB journal : official publication of the Federation of American Societies for Experimental BiologyNeutrophilia in severe asthma is reduced in Ormdl3 overexpressing mice.PMC9990076R01AI125433T32 GM144294R01 AI125433F31 HL154486Z01 DK056014P30 CA016059Martin RKWeigel CProia RLMilstien SBrown RDRPalladino ENDGreen CDTharakan ASpiegel SJames BNfalseNeutrophilia in severe asthma is reduced in Ormdl3 overexpressing mice.Genome-wide association studies have linked the ORM (yeast)-like protein isoform 3 (ORMDL3) to asthma severity. Although ORMDL3 is a member of a family that negatively regulates serine palmitoyltransferase (SPT) and thus biosynthesis of sphingolipids, it is still unclear whether ORMDL3 and altered sphingolipid synthesis are causally related to non-Th2 severe asthma associated with a predominant neutrophil inflammation and high interleukin-17 (IL-17) levels. Here, we examined the effects of ORMDL3 overexpression in a preclinical mouse model of allergic lung inflammation that is predominantly neutrophilic and recapitulates many of the clinical features of severe human asthma. ORMDL3 overexpression reduced lung and circulating levels of dihydrosphingosine, the product of SPT. However, the mos2023-01-01T00:00:00Z2023 Mar2025-04-04T00:35:02.915Z2025-02-19T01:41:31.084ZS-EPMC99900763675341210.1096/fj.202201821R