Deficiency of Toll-like receptor 2 is a driver of sex-related compositional and structural rearrangements of membrane lipids.

The behavior and function of membrane microdomains is shaped by the intricate liaison between the most complex glycosphingolipids-gangliosides, cholesterol and specific classes of transmembrane proteins. Toll-like receptor 2 (TLR2), a pattern recognition receptor localized in lipid rafts, is implicated in different membrane-associated events, some of which overlap between gangliosides and TLR2, such as pathogen recognition and neuroinflammation. Aiming to determine whether TLR2 deficiency influences on the composition and arrangement of membrane lipids, we examined cortical tissue of TLR2-deficient and control mice by in-depth glycolipidomic profiling along with transcriptomic analysis of genes involved in ganglioside and cholesterol metabolism. A multi-level experimental approach, including powerful high-resolution mass spectrometry techniques, provided a detailed lipidomic data and elaborate structural characterization of brain gangliosidome and sterolome in TLR2 deficiency. The results demonstrate the presence of distinct brain glycolipidomic and sterol pattern as well as lipid redistribution within the membrane fractions in TLR2 deficiency. In addition, the findings speak in favor of a sex-specific structural and functional partnership of TLR2, gangliosides and cholesterol in the brain tissue that may act as a connection point integrating extracellular stimuli and modulating neuroimmune response in a sex-dependent manner.