Juan Pablo Rodríguez

Lipids are no longer viewed merely as membrane components or energy stores, but as dynamic regulators of immune cell activation, adaptation, and fate. The articles assembled in this Research Topic extend this view by converging on a central principle: the immunological effects of lipids are determined not by abundance alone, but by molecular identity, metabolic routing, cellular source, tissue localization, and timing. In this sense, context is not simply a modifier of lipid signaling; it is part of the mechanism. This principle emerges across the four biological settings represented in the collection-macrophage metabolism, liver injury, tumor-associated immune dysfunction, and inflammatory skin disease-where lipid pathways can preserve homeostasis or promote pathology depending on when and where they operate (Figure 1). Bamgbose et al. (1) provide a broad conceptual framework for understanding these context-dependent effects. Their review examines how macrophages channel fatty acids toward mitochondrial β-oxidation, glycerolipid synthesis and lipid-droplet storage, sphingolipid production, or polyunsaturated fatty acidderived mediators. These routes support distinct and sometimes opposing outcomes, including inflammatory activation, efferocytosis, resolution of inflammation, metabolic adaptation, and lipotoxic dysfunction. Lipin-1 illustrates this complexity particularly well. Positioned at a branch point between phosphatidic acid and diacylglycerol metabolism, and also acting through non-enzymatic regulatory functions, lipin-1 can amplify inflammatory signaling in lipid-loaded macrophages while supporting mitochondrial fitness and efferocytosis in pro-resolving states. The relevant therapeutic question is therefore not whether a pathway is intrinsically inflammatory, but how lipid flux is organized in a defined macrophage population and tissue niche. The study by Xu et al. (2) reinforces this principle through a model in which loss of group VIA calciumindependent phospholipase A2 (iPLA2β/PLA2G6) interacts with environmental exposure, age, and sex. In mice naturally exposed to pathogens, global PLA2G6 deficiency aggravated hepatocellular apoptosis, inflammatory fibrosis, and susceptibility to endotoxin-induced injury in both sexes. However, defective hepatic glycerolipid synthesis, reduced triacylglycerol and lipoprotein secretion, and reduced adiposity were most evident in males. These findings reveal a homeostatic role for iPLA2β and caution against interpreting lipid-metabolizing enzymes as uniformly pathogenic targets. They also emphasize that sex and microbial environment can uncover phenotypes that remain muted under specific-pathogen-free conditions. More broadly, the work argues for experimental designs that integrate lipid metabolism with biological variables often treated as secondary. Two additional contributions demonstrate how locally generated lipids can organize pathological immune niches. Turner et al. ( 3) investigate the autotaxin-lysophosphatidic acid (ATX-LPA) axis in liver metastases from uveal melanoma, a disease characterized by hepatic tropism and limited responsiveness to conventional immunotherapy. Autotaxin is a secreted ectoenzyme that generates extracellular LPA, an immunosuppressive lipid mediator that can limit cytotoxic CD8 + T-cell function through LPAR5. In this setting, the authors show that LPA induces low-level but persistent ERK phosphorylation in effector CD8 + T cells, with dynamics distinct from canonical T-cell receptor signaling, and that loss of LPAR5 improves CD8 + T-cell survival and cytokine function during chronic stimulation. Together with the detection of elevated ATX transcripts in tumor-associated hepatic CD8 + T cells, these findings identify ATX-LPA signaling as a plausible contributor to immune dysfunction in the metastatic liver. The study also highlights the potential of combining pathway-selective immune intervention with liver-directed cytoreduction such as percutaneous hepatic perfusion with melphalan, while appropriately leaving the efficacy and optimal sequencing of such combinations for future investigation. Miki et al. ( 4) extend the theme to the epidermis by identifying a PLA2G2F-lysoplasmalogen axis that links keratinocyte lipid metabolism with type 2 inflammation and itch in atopic dermatitis. PLA2G2F, induced by type 2 cytokines, generates lysoplasmenylethanolamine (P-LPE). Genetic deletion of Pla2g2f reduced keratinocyte IL-33 expression, epidermal hyperplasia, serum IgE, type 2 inflammation, and scratching in mice. Pharmacological inhibition or enzymatic degradation of P-LPE also suppressed itch, whereas exogenous P-LPE partially restored scratching in deficient animals. Importantly, P-LPE was elevated in the stratum corneum of patients and correlated with disease severity. This work therefore connects a defined lipid product to epithelial alarm signaling, a clinically relevant symptom, and a potential biomarker, while illustrating the advantages of tissue-localized therapeutic intervention. Viewed together, these studies reveal lipid signaling as a spatially organized network that connects intracellular metabolic decisions with communication between immune and structural cells. They also expose a recurring translational challenge. Broad inhibition of lipid synthesis or lipid-metabolizing enzymes may disrupt protective buffering, membrane homeostasis, efferocytosis, or tissue repair. Greater therapeutic precision will require discrimination among enzymatic and non-enzymatic functions, lipid species, receptors, cellular sources, and disease stages. Strategies such as lymphocyte-selective LPAR5 inhibition, topical targeting of PLA2G2F, macrophage-directed modulation of lipid-routing nodes, or interventions informed by sex and microbial exposure exemplify this shift from pathway suppression to context-specific control. The next phase of this field should combine quantitative lipidomics with...

Background: Ophidism is a globally neglected health problem. In Argentina, Crotalus durissus terrificus (C.d.t., South American rattlesnake) is one of the species of greatest medical importance since its venom contains mainly crotoxin (CTX), a potent enzyme–toxin with PLA₂ activity, which is responsible for its high lethality. Objective: In this work, we aimed to generate nanovenoms (NVs), complexes formed by CTX adsorbed onto 150 nm silica nanoparticles (SiNPs), and to study their physicochemical, biological, and immunomodulatory activities for potential use as adjuvants (ADJs) in antivenom (AV) production. Methods: CTX was isolated and corroborated by SDS-PAGE. Then, CTX was adsorbed on the synthetized Stöber SiNPs’ surfaces, forming a monolayer and retaining its biological activity (as observed by the MTT cell proliferation assay using the THP-1 cell line). Results: Immunomodulatory activity revealed a high pro-inflammatory (IL-1β) response induced by SiNPs followed by NVs. In the case of the anti-inflammatory response, NVs presented significant differences for TGF-β only after cell activation with LPS. No significant differences were observed in IL-10 levels. Conclusions: Thus, these results suggest that NVs together with SiNPs could increase immunogenicity and enhance immune response, turning them into potential tools for the generation of new antivenoms.

Microglia, the resident macrophage-like population in the CNS, plays an important role in the pathogenesis of many neurodegenerative disorders. Nectandra genus is known to produce different metabolites with anti-inflammatory, anti-oxidant and analgesic properties. Although the species Nectandra angustifolia is popularly used for the treatment of different types of inflammatory processes, its biological effects on neuroinflammation have not yet been addressed. In this study, we have investigated the role of a Nectandra angustifolia ethanolic extract (NaE) in lipopolysaccharide (LPS)-induced neuroinflammation in vitro and in vivo. In LPS-activated BV2 microglial cells, NaE significantly reduced the induced proinflammatory mediators TNF-α, IL-1β, IL-6, COX-2 and iNOS, as well as NO accumulation, while it promoted IL-10 secretion and YM-1 expression. Likewise, reduced CD14 expression levels were detected in microglial cells in the NaE+LPS group. NaE also attenuated LPS-induced ROS and lipid peroxidation build-up in BV2 cells. Mechanistically, NaE prevented NF-κB and MAPKs phosphorylation, as well as NLRP3 upregulation when added before LPS stimulation, although it did not affect the level of some proteins related to antioxidant defense such as Keap-1 and HO-1. Additionally, we observed that NaE modulated some activated microglia functions, decreasing cell migration, without affecting their phagocytic capabilities. In LPS-injected mice, NaE pre-treatment markedly suppressed the up-regulated TNF-α, IL-6 and IL-1β mRNA expression induced by LPS in brain. Our findings indicate that NaE is beneficial in preventing the neuroinflammatory response both in vivo and in vitro. NaE may regulate microglia homeostasis, not only restraining activation of LPS towards the M1 phenotype but promoting an M2 phenotype.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target.

Macrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachidonic acid (AA) among glycerophospholipids and its subsequent release and conversion into eicosanoids in response to inflammatory stimuli such as zymosan, constitutes one of the most studied models. In this work, we used liquid and/or gas chromatography coupled to mass spectrometry to study the changes in the levels of membrane glycerophospholipids of mouse peritoneal macrophages and the implication of group IVA cytosolic phospholipase A₂ (cPLA₂α) in the process. In the experimental model used, we observed that the acute response of macrophages to zymosan stimulation involves solely the cyclooxygenase-1 (COX-1), which mediates the rapid synthesis of prostaglandins E₂ and I₂. Using pharmacological inhibition and antisense inhibition approaches, we established that cPLA₂α is the enzyme responsible for AA mobilization. Zymosan stimulation strongly induced the hydrolysis of AA-containing choline glycerophospholipids (PC) and a unique phosphatidylinositol (PI) species, while the ethanolamine-containing glycerophospholipids remained constant or slightly increased. Double-labeling experiments with ³H- and ¹⁴C-labeled arachidonate unambiguously demonstrated that PC is the major, if not the exclusive source, of AA for prostaglandin E₂ production, while both PC and PI appeared to contribute to prostaglandin I₂ synthesis. Importantly, in this work we also show that the COX-1-derived prostaglandins produced during the early steps of macrophage activation restrict tumor necrosis factor-α production. Collectively, these findings suggest new approaches and targets to the selective inhibition of lipid mediator production in response to fungal infection.