Vesículas extracelulares enriquecidas com ácidos graxos na modulação imunológica: impacto na atividade de macrófagos estimulados por partículas virais do SARS-CoV-2”

Abstract

COVID-19, a disease caused by the etiological agent SARS-CoV-2, can progress to clinical conditions characterized by dysregulated immune responses, resulting in a hyperinflammatory environment. Therefore, developing therapeutic strategies to control inflammation is essential. Extracellular vesicles (EVs) are membrane nanostructures that act as intercellular messengers and are produced by various cells, including macrophages. These vesicles carry different biomolecules and can modulate immune responses. Fatty acids (FAs) are components of structural lipids in plasma membranes and play a relevant role in regulating the immune response. The objective of the present study was to develop EVs enriched with different classes of fatty acids possessing immunomodulatory potential in inflammatory contexts. To this end, monocytes from the THP-1 lineage were differentiated into M0 macrophages and subsequently polarized into M1 (LPS + IFN-$\gamma$) and M2 (IL-4 + IL-13) phenotypes. Extracellular vesicles (EVs) were isolated from macrophages incubated with different classes of exogenous FAs (saturated, unsaturated, and long-chain). The isolated macrophage EVs (natural and FA-enriched) were characterized using Nanoparticle Tracking Analysis (NTA) (size, concentration, and distribution), Zeta Potential (colloidal stability and surface charge), and Flow Cytometry (marker proteins).M0 macrophages were prophylactically treated with EVs (natural or FA-enriched) and challenged with inflammatory stimuli (LPS or inactivated SARS-CoV-2 viral particles), followed by assessment of the inflammatory cytokine profile. Our results demonstrate that different classes of exogenous FAs promote changes in the lipid expression profile of polarized macrophage membranes. FA-enriched EVs increased mitochondrial activity; those enriched with saturated FAs induced the production of pro-inflammatory cytokines, whereas those enriched with polyunsaturated fatty acids (PUFAs) reduced this production. This study demonstrates that the incorporation of exogenous FAs influences membrane remodeling, impacting the lipid profile and immunological functions of macrophage-derived EVs, thereby modulating the inflammatory context.