Increased de novo sphingolipid biosynthesis causes a dramatic increase in CD11b+, CD11c+ population in a novel mouse model

Authors

• S Majumder
• G Tuymetova
• C Giannouli
• TM Dunn
• RL Proia

Abstract

Aberrant sphingolipid homeostasis has been implicated in different pathologic conditions, such as in aging, neurodegenerative and metabolic diseases and inflammation. Serine palmitoyltransferase (SPT) catalyzes the first and rate-limiting step in de novo sphingolipid biosynthetic pathway. Our understanding on cellular response to increased sphingolipid levels is lacking. Here we report the development of a novel model system where generic expression of active SPT enzyme is under the control of an inducible promoter. Upon induction, expression of this transgene has been detected in different tissues. Dose dependent expression of the transgene resulted in corresponding increase in enzymatic activity. Compared to control, complex plasma sphingolipid levels were significantly elevated in heterozygous mice, suggesting that products of the transgene are efficiently converted to complex sphingolipids. Expression of fusion SPT transgene showed a robust and dose dependent increase in CD11b+, CD11c+, Ly6C+ and Ly6G+ positive population in blood, bone marrow and in spleen. However this unique population lacks other conventional dendritic cell activation makers such as CD80, CD86 and MHCII. Our initial observation indicate that expansion of this population has undetectable impact on number of B or T cell population in blood, bone marrow or in spleen. The mechanism by which increased sphingolipid synthesis causes the dramatic increase of the myeloid population is under investigation.

Scientific Focus Area: Cell Biology

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