OXYLIPINS IN INFLAMMATION AND INFLAMMATION RESOLUTION IN THE ACID SPHINGOMYELINASE DEFICIENCY

Acid Sphingomyelinase Deficiency (ASMD) is caused by mutations in the gene encoding for acid sphingomyelinase (ASM). The mutations impair the function of this sphingomyelin (SM)-metabolic enzyme, leading to SM accumulation in endolysosomes and plasma membrane. In patients suffering from the infantile neurovisceral ASMD (type A), characterized by short life expectancy, SM accumulates in brain cells, promoting chronic neuroinflammation and neurodegeneration.
In the context of ASMD, neuroinflammation has been considered a consequence of neuronal death, but recent work from our group has demonstrated that it is an early event in the disease and that dysfunctional microglia contribute to trigger neuronal death. Nevertheless, the role of astrocytes in this process remains unclear. Furthermore, little is known about the alterations in inflammation and inflammation-resolution pathways that may drive the development of chronic neuroinflammation.
Oxylipins are oxidized polyunsaturated fatty acids that participate in inflammation and inflammation resolution. In the brain, they are maintained in a balance between active (free) and inactive (esterified) forms. We have recently found the brain ‘oxylipidome’ to be different in mice lacking ASM (ASMko), which mimic ASMD type A, compared to wild type mice. Moreover, there is an increase in oxylipin esterification in ASMko cultured neurons, and we observe a decrease of inflammation and inflammation-resolution signalling in SM-accumulating cultured astrocytes. Preliminary results indicate that increasing free oxylipin levels might restore inflammation and inflammation-resolution signalling in vitro. These data suggest an imbalance towards oxylipin inactivation in the ASMko brain and support oxylipin modulation as a potential therapeutical target for neurovisceral ASMD.