Biology subjects

Morel, L.

Publications and source records attributed to Morel, L..

8 recordsLinked to original sources

bioRxiv2025

Maternal n-3 PUFA deficiency alters brain fatty acid and oxylipin profiles across perinatal development in offspring

Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), are essential for optimal neurodevelopment through their effect on neuronal proliferation, neurite outgrowth and synaptogenesis. Emerging evidence highlights that brain PUFAs are metabolized in oxylipins, the bioactive oxidized PUFA metabolites known to regulate inflammatory processes. Recent data highlighted that both PUFA and oxylipin profiles are modulated in the adult male brain by dietary PUFA content. However, little is known on the impact of maternal dietary n-3 PUFA intake during the perinatal period and the neurodevelopmental profile of brain fatty acids and associated oxylipins in offspring, and whether these effects differ between sexes. To address this question, we first measured fatty acid levels in the placenta and embryonic brain of male and female offspring of mothers fed a sufficient or deficient diet in n-3 PUFAs at embryonic day (E)17.5. Then, fatty acids and oxylipins were measured at different post-natal stages, in the brain at P0 and P7, and in the hippocampus at P14 and P21, in both male and female offspring. Our results show that maternal n-3 PUFA dietary deficiency alters fatty acid profiles as early as E17.5 in both the placenta and the brain. Furthermore, dietary intervention affects both fatty acid and oxylipin profiles throughout postnatal brain development, with notable sex-specific differences. These findings underscore the critical importance of adequate maternal n-3 PUFA intake during the perinatal period for maintaining an optimal PUFA and oxylipin profiles, with potential implications for fetal and postnatal brain development.

neuroscience↗

bioRxiv2024

Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice

Glutamine metabolism is essential for T cell activation and functions. The inhibition of glutaminolysis impairs Th17 cell differentiation and alters Th1 cell functions. There is evidence for an active glutaminolysis in the immune cells of lupus patients. Treatment of lupus-prone mice with glutaminolysis inhibitors ameliorated disease in association with a reduced frequency of Th17 cells. This study was performed to determine the role of glutaminolysis in murine Tfh cells, a critical subset of helper CD4+ T cells in lupus that provide help to autoreactive B cells to produce autoantibodies. We showed that lupus Tfh present a high level of glutamine metabolism. The pharmacological inhibition of glutaminolysis with DON had little effect on the Tfh cells of healthy mice, but it reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production, germinal center B cell dynamics, as well as a reduction of the frequency of atypical age-related B cells and plasma cells. Accordingly, profound transcriptomic and metabolic changes, including an inhibition of glycolysis, were induced in lupus Tfh cells by DON, while healthy Tfh cells showed little changes. The T cell-specific inhibition of glutaminolysis by deletion of the gene encoding for the glutaminase enzyme GLS1 largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with little effect in a congenic control background. These results were confirmed in an induced model of lupus. Finally, we showed that T cell-specific Gls1 deletion impaired T- dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results demonstrated a greater intrinsic requirement of lupus Tfh cells for their helper functions, and they suggest that targeting glutaminolysis may be beneficial to treat lupus.

immunology↗

bioRxiv2024

Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the production of pathogenic autoantibodies depends on T follicular helper (TFH) cells. This study was designed to investigate the mechanisms by which inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reduces the expansion of TFH cells and the associated autoantibody production in lupus-prone mice. Integrated cellular, transcriptomic, epigenetic and metabolic analyses showed that 2DG reversed the enhanced cell expansion and effector functions, as well as mitochondrial and lysosomal defects in lupus TFH cells, which include an increased chaperone-mediated autophagy induced by TLR7 activation. Importantly, adoptive transfer of 2DG-reprogrammed TFH cells protected lupus-prone mice from disease progression. Orthologs of genes responsive to 2DG in murine lupus TFH cells were overexpressed in the TFH cells of SLE patients, suggesting a therapeutic potential of targeting glycolysis to eliminate aberrant TFH cells and curb the production of autoantibodies inducing tissue damage.

immunology↗

bioRxiv2024

Contribution of rat insular cortex to stimulus-guided action

Anticipating rewards is fundamental for decision-making. Animals often use cues to assess reward availability and to make predictions about future outcomes. The gustatory region of the insular cortex (IC), the so-called gustatory cortex, has a well-established role in the representation of predictive cues, such that IC neurons encode both a general form of outcome expectation as well as anticipatory outcome-specific knowledge. Here, we used Pavlovian-instrumental transfer (PIT) in male rats to assess if the IC is also required for predictive cues to exert both a general and specific influence over instrumental actions. Chemogenetic inhibition of IC abolished the ability of a reward-predictive stimulus to energize instrumental responding for reward. This deficit in general transfer was evident whether the same or different outcomes were used in the Pavlovian and instrumental conditioning phases. We observed a similar deficit in specific PIT, such that rats with IC inhibition failed to use a reward-predictive stimulus to guide choice toward actions that deliver the same food reward. Finally, we show that rats with IC inhibition also fail to show outcome-selective reinstatement. Together, these data suggest a crucial role for IC in the representation of appetitive outcomes, and particularly in using this representation to guide instrumental action. SIGNIFICANCE STATEMENTAnimals frequently use cues to infer the availability of rewards and to make predictions about future outcomes. The influence of these predictive cues on behaviour can be studied using Pavlovian-instrumental transfer (PIT), in which Pavlovian outcome expectancies can elevate (general PIT) or selectively guide (specific PIT) instrumental actions. In the current study, we show that chemogenetic inhibition of the gustatory region of insular cortex (IC) abolishes both general and specific transfer, as well as the selectivity of outcome-induced reinstatement. These results demonstrate a critical role for the IC in the representation of appetitive outcomes and significantly contribute to a broader understanding of the cortical bases of PIT.

neuroscience↗

bioRxiv2024

Dietary tryptophan and genetic susceptibility expand gut microbiota that promote systemic autoimmune activation

Tryptophan modulates disease activity and the composition of microbiota in the B6.Sle1.Sle2.Sle3 (TC) mouse model of lupus. To directly test the effect of tryptophan on the gut microbiome, we transplanted fecal samples from TC and B6 control mice into germ-free or antibiotic-treated non-autoimmune B6 mice that were fed with a high or low tryptophan diet. The recipient mice with TC microbiota and high tryptophan diet had higher levels of immune activation, autoantibody production and intestinal inflammation. A bloom of Ruminococcus gnavus (Rg), a bacterium associated with disease flares in lupus patients, only emerged in the recipients of TC microbiota fed with high tryptophan. Rg depletion in TC mice decreased autoantibody production and increased the frequency of regulatory T cells. Conversely, TC mice colonized with Rg showed higher autoimmune activation. Overall, these results suggest that the interplay of genetic and tryptophan can influence the pathogenesis of lupus through the gut microbiota.

immunology↗

bioRxiv2022

Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis

ObjectiveAn appreciation of factors that lead to tubular injury in lupus nephritis is lacking. Iron accumulates in the kidney tubules of nephritic patients and lupus-prone nephritic mice. Ferroptosis is a druggable, iron-dependent form of cell death that has received little attention in lupus nephritis. This study investigated whether intra-renal ferroptosis is a target for intervention in lupus nephritis. MethodsKidneys of lupus nephritis patients and two spontaneous murine models of lupus nephritis were characterized for ferroptosis using protein, RNA, and lipidomics-based approaches. Susceptibility of heavy chain ferritin (FtH1; an essential iron sequestration protein) deficient proximal tubular epithelial cells (PTECs) was studied using nephrotoxic serum nephritis and FtH1 knockdown human PTECs. The benefit of Liproxstatin-2, a novel second-generation ferroptosis, was evaluated using human PTECs exposed to lupus nephritis patients serum. ResultsHuman and murine nephritic kidneys have the characteristic markers of ferroptosis, such as 4-hydroxynonenal and acyl-CoA synthetase long-chain family member 4, mainly in the tubular segments. Murine kidneys showed impairment in the glutathione synthesis pathway, decreased expression of glutathione peroxidase 4, a glutathione-dependent ferroptosis inhibitor, and characteristic ferroptotic lipid signature. Loss of FtH1 increased PTEC pathology independent of glomerular injury. These findings were recapitulated in human PTECs. Of translational relevance, Liproxstatin-2 demonstrated a prophylactic and therapeutic benefit in mitigating lupus nephritis patient serum-induced PTEC ferroptosis. ConclusionOur findings highlight tubular cell ferroptosis as a pathological feature in human and murine lupus nephritis and identify ferroptosis inhibitors as potential novel adjunct therapeutics to treat lupus nephritis.

immunology↗

bioRxiv2020

From taxonomic to functional dark diversity: exploring the causes of potential biodiversity and its implications for conservation

O_LIDark diversity is an emerging and promising concept proposed to estimate the recruitment potential of natural communities and guide conservation and restoration policies. It represents all the species that could be present in a community due to favourable environmental conditions, but are currently lacking. To date, experimental approaches only measured taxonomic dark diversity, mainly based on species coexistence, which relies partly on neutral processes. Thus, these approaches may fail to identify the biodiversity which is lacking for deterministic reasons, and can hence hardly bring out suitable restoration methods. C_LIO_LIHere, we propose a novel method to estimate dark diversity, which is based on more deterministic coexistence: the coexistence of species functional features. We adapted the Beals co-occurrence index using functional groups, and we estimated functional dark diversity based on coexistence of functional groups. We then made use of functional dark diversity to address a persistent issue of restoration ecology: how does passive rewilding impact the ecological integrity of recovered communities? We compared spontaneous, secondary woodlands with ancient forests, in terms of taxonomic and functional dark diversity of vascular plants and spiders. C_LIO_LIOur results indicated that functional dark diversity does not equate to taxonomic dark diversity. Considering plants, recent woodlands surprisingly harboured less functional dark diversity than ancient forests, while they had a very similar amount of taxonomic dark diversity. Concerning spiders, recent woodlands harboured a similar amount of functional dark diversity as ancient forests, but more taxonomic dark diversity. Also, the composition of functional dark diversity differed between forest types, shedding light on their past assembly processes and unveiling their potential for conservation and effective restoration. C_LIO_LISynthesis and applications. Functional dark diversity brings novel perspectives for ecological diagnostic and restoration. Combined to taxonomic dark diversity, it enables to identify easily the deterministic constrains which limit the re-assembly of ecological communities after land-use changes and to predict the realistic, possible establishments of functional features. Here, we showed that spontaneous woodlands can have very similar, sometimes even higher, ecological integrity than that of ancient forests, and hence may be valuable habitats to be conserved from an ecological perspective. C_LI

ecology↗

bioRxiv2019

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.\n\nOne Sentence SummaryLow maternal omega-3 fatty acids intake impairs microglia-mediated synaptic refinement via 12-HETE pathway in the developing brain.

neuroscience↗