The acid sphingomyelinase inhibitor imipramine enhances the release of UV photoproduct‐containing DNA in small extracellular vesicles in UVB‐irradiated human skin

Abstract Nucleic acids, lipids, and other cell components can be found within different types of extracellular vesicles (EVs), which include apoptotic bodies (ABs), large extracellular vesicles (LEVs), and small extracellular vesicles (SEVs). Release of LEVs from cells can be reduced by genetic or pharmacological inhibition of the enzyme acid sphinogomyelinase (aSMase), and indeed several studies have demonstrated a role for the clinically approved aSMase inhibitor imipramine in blocking LEV release, including in response to UVB exposure. Given that exposure of keratinocytes to UVB radiation results in the generation of UVR photoproducts in DNA that can subsequently be found in association with ABs and SEVs, we examined how imipramine impacts the release of extracellular DNA containing UVR photoproducts at an early time point after UVR exposure. Using several different model systems, including cultured keratinocytes in vitro, discarded human surgical skin ex vivo, and skin biopsies obtained from treated human subjects, these pilot studies suggest that imipramine treatment stimulates the release of CPD‐containing, SEV‐associated DNA. These surprising findings indicate that LEV and SEV generation pathways could be linked in UVB‐irradiated cells and that imipramine may exacerbate the systemic effects of extracellular UVR‐damaged DNA throughout the body.