Biology subjects

Aljadeed, N. M.

Publications and source records attributed to Aljadeed, N. M..

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↗

bioRxiv2023

Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.

Inflammasomes are multi-protein complexes assembled by NOD-like receptor (NLR) family of proteins, which play critical roles in infectious, inflammatory and metabolic diseases. The assembly of the NLRP3 inflammasome is triggered upon recognition of an apt stimulus by the sensor protein, resulting in binding to pro-caspase-1 via the adaptor protein ASC. Inflammasome activation results in the maturation of the precursor forms of cytokines IL-1{beta} and IL-18, along with caspase-1-dependent pyroptosis, a pro-inflammatory form of cell death. Emerging evidence suggests the involvement of lipid metabolism in inflammasome activation; however, the precise mechanisms by which lipids regulate the NLRP3 inflammasome remain ambiguous. A multi-enzyme protein, fatty acid synthase (FASN) is a central regulator of lipid metabolism partaking an essential role in fatty acid biosynthesis pathway by catalysing the production of palmitic acid. Palmitic acid acts as a precursor to long-chain fatty acids and additionally regulates cellular functions by palmitoylation, a process in which palmitate is reversibly added to cysteine residues of target proteins, modifying protein localization and function. Here, we undertook a pharmacological approach to investigate the roles of fatty acid biosynthetic pathway in NLRP3 inflammasome activation. Our results demonstrated that inhibition of FASN in primary mouse and human macrophages abrogates the activation of the NLRP3 inflammasome, resulting in blunted caspase-1 activation. Furthermore, this phenomenon relied on protein palmitoylation as in vitro and in vivo abrogation of palmitoylation similarly reduced NLRP3 activation, which could be restored by exogenously supplementing palmitate in cultured cells. Consequently, an acyl biotin exchange assay corroborated NLRP3 palmitoylation. Notably, activation of the dsDNA sensing AIM2 inflammasome remained unaltered when either FASN or palmitoylation was blocked. These results therefore highlight the pivotal role of FASN and palmitoylation, shedding new mechanistic insights into the activation of the NLRP3 inflammasome.

immunology↗