Biology subjects

Olona, A.

Publications and source records attributed to Olona, A..

3 recordsLinked to original sources

bioRxiv2026

Lipid droplet accumulation drives glutamine-dependent NLRP3 inflammasome activation

The NLRP3 inflammasome is implicated in the pathogenesis of many inflammatory and metabolic diseases. Although metabolic cues can shape NLRP3 inflammasome activation, the role of lipid metabolism in this response is poorly understood. Lipids are essential for energy and redox homeostasis, membrane biogenesis, and diverse cellular processes. However, excessive accumulation of lipids such as free fatty acids can be highly cytotoxic. Consequently, surplus free fatty acids are esterified into triglycerides and cholesteryl esters, which are then stored within lipid droplets (LDs). Interestingly, transcriptomic data analyses revealed that macrophages exposed to inflammasome-activating stimulus undergo a broad metabolic rewiring favouring lipid storage, suggesting a link between LDs and inflammasome response. Here, we show that LD accumulation actively promotes NLRP3 inflammasome activation. Increasing LD abundance, either by fatty acid supplementation or by inhibition of lipolysis, led to robust caspase-1 activation and IL-1{beta} release both in vitro and in vivo. Mechanistically, LD expansion promoted cellular reorganisation resulting in the formation of peri-droplet mitochondria, a distinct mitochondrial subpopulation which exhibited elevated membrane potential and increased ATP-linked respiration. Furthermore, LD-rich macrophages underwent metabolic reconfiguration whereby they exhibited a pronounced reliance on pyruvate and glutamine metabolism, but not fatty acid oxidation, to sustain mitochondrial bioenergetics. Surprisingly, inflammasome activation was found dependent predominantly on glutaminolysis, highlighting a key role for glutamine catabolism in LD-rich cells. Collectively, these findings identify a glutamine-dependent pathway as a key driver linking excess lipid storage to NLRP3 inflammasome, with profound implications in metabolic diseases.

immunology↗

bioRxiv2026

Distinct lipid transport proteins are regulated by innate immune stimuli

Lipid transport plays a critical role in the distribution of lipids across subcellular compartments. This is pivotal during infection and other stress stimuli that increase metabolic demands. While lipid biosynthesis is regulated by immune stimuli, whether immune signalling also influences lipid transport mechanisms remains unexplored. Here, we demonstrate that TLR signalling impacts the gene expression of lipid transport proteins in human monocytic THP-1 cell line and compare it to the expression in primary bone marrow-derived mouse macrophages. Our data demonstrates that TLR4 signalling selectively modulates the expression of oxysterol-binding protein-related proteins (ORPs), a key family of proteins that transport lipids between organelles. Remarkably, TLR4 activation led to the downregulation of several ORP family members in human THP1-derived macrophages. However, this response was less profound in mouse macrophages. In contrast, the expression of steroidogenic acute regulatory domain (STARD) proteins, many of which transport lipids between mitochondria and other compartments, remained broadly unaffected. Moreover, IFNG, a cytokine that plays a key role in the immune response, did not considerably impact human ORP or STARD expression levels, either alone or in combination with LPS. Together, these results reveal that TLR signalling exerts selective and critical control over lipid trafficking pathways with important species-specific differences. These findings provide new insights into the crosstalk between immune signalling and lipid metabolism, which may offer novel targets to treat diseases characterized by dysregulated lipid pathways.

immunology↗

bioRxiv2020

Cardiac glycosides cause selective cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis

Cardiac glycosides (CGs) inhibit the Na+,K+-ATPase and are widely prescribed medicines for chronic heart failure and cardiac arrhythmias. Recently, CGs have been described to induce inflammasome activation in human macrophages, suggesting a cytotoxicity that remains to be elucidated in tissues. Here we show that human monocyte-derived macrophages (hMDMs) undergo cell death following incubation with nanomolar concentrations of CGs, and in particular with ouabain (IC50=50 nM). The ouabain-induced cell death is more efficient in hMDMs compared to non-adherent PBMC populations and is through on-target inhibition of Na,K-ATPAse activity, as it causes an intracellular depletion of K+, while inducing accumulation of Na+ and Ca2+ levels. Consistently, the cell-death caused by these ion imbalances can be rescued by addition of potassium chloride in hMDMs. Strikingly, white adipose tissue (WAT) explants from morbidly obese patients cultured with nanomolar concentrations of ouabain causes depletion of macrophages, decreases type VI collagen levels, and ameliorates insulin-sensitivity ex vivo. These results suggest that the usage of nanomolar concentration of CGs can be an attractive therapeutic avenue in metabolic syndrome characterised by pathogenic infiltration and activation of macrophages.

immunology↗