Biology subjects

Lucas, S.

Publications and source records attributed to Lucas, S..

11 recordsLinked to original sources

bioRxiv2026

Platelet GARP-dependent activation of TGF-β1 limits inflammation and promotes cardiac repair after myocardial infarction

Platelets are increasingly recognized as active regulators of inflammation beyond their canonical hemostatic functions. Although platelets rapidly accumulate in the injured myocardium after myocardial infarction (MI), the mechanisms by which they coordinate the inflammatory response remain poorly understood. Glycoprotein A repetitions predominant (GARP) is a membrane receptor that presents latent transforming growth factor-{beta}1 (TGF-{beta}1) on activated platelets and supports its activation. Given the central role of TGF-{beta}1 in inflammation and tissue repair, we hypothesized that platelet GARP-dependent activation of TGF-{beta}1 regulates inflammatory resolution and repair after MI. Using mice with megakaryocyte-and platelet-specific Garp deletion, we demonstrate that loss of platelet GARP selectively impaired generation of bioactive TGF-{beta}1 without altering platelet reactivity. Following permanent coronary artery ligation, platelet-specific Garp deficiency markedly increased mortality from ventricular rupture and exacerbated adverse left ventricular remodeling, independent of initial infarct size. Transcriptomic and histological analyses revealed heightened endothelial cell activation, increased leukocyte recruitment, delayed inflammatory resolution, and defective extracellular matrix deposition in the absence of platelet GARP. Mechanistically, platelet GARP-dependent TGF-{beta}1 signaling restrained endothelial activation after MI. Together, these findings identify platelet GARP-mediated activation of TGF-{beta}1 as a critical platelet-intrinsic counter-regulatory checkpoint that limits endothelial-driven inflammation and promotes infarct stabilization. Our study reveals an unexpected protective immunoregulatory function of platelets in cardiac repair after ischemic injury.

pathology↗

bioRxiv2025

The phosphate exporter XPR1 regulates a gasdermin D-independent mature IL-1β secretion pathway in LPS-stimulated human monocytic cells

The inflammatory cytokine interleukin (IL)-1{beta} is a leaderless protein that is not secreted via the classical endoplasmic reticulum-Golgi pathway but instead is secreted during pyroptosis, a form of caspase-dependent inflammatory cell death mediated by gasdermin D (GSDMD) cleavage and pore formation at the plasma membrane. However, human monocytes can secrete IL-1{beta} in the absence of cell death, and the contribution of GSDMD in this secretory pathway is not established. Here, we identify two mechanisms of mature IL-1{beta} secretion by living human monocytic cells: a rapid, GSDMD-dependent pathway and a slower, GSDMD-independent pathway. Using a CRISPR-Cas9 loss-of-function screen, we identified XPR1 (Xenotropic and Polytropic retrovirus Receptor 1) as a key regulator of the GSDMD-independent pathway. XPR1 is the only phosphate exporter identified in metazoans and has no previously described function in cytokine secretion. XPR1 invalidation in GSDMD-/- monocytic cells impaired IL-1{beta} secretion. We further show that this regulatory function requires cell-surface expression of XPR1 and is linked to its phosphate export activity. Our results reveal a previously undescribed mechanism of IL-1{beta} secretion by living human monocytic cells, independent of GSDMD and unexpectedly linked to phosphate homeostasis. Deciphering this pathway could lead to new therapeutic modalities for IL-1{beta}-driven inflammatory diseases.

immunology↗

bioRxiv2025

FLASH or flare: variable intestinal toxicity results in a mouse model following proton pencil beam scanning irradiation on a clinical superconducting synchrocyclotron

Background and aimsUltra-high dose rate (FLASH) irradiation is a promising technique to reduce radiation-induced normal tissue toxicities while preserving antitumor efficacy. We evaluated the feasibility and intestinal sparing potential of FLASH irradiation using a clinical synchrocyclotron-based proton therapy system generating a pulsed beam. Material and methodsC57BL/6J mice received abdominal irradiation (2x2 cm) in transmission mode at FLASH (>60 Gy/s) or conventional (CONV, 0.5 Gy/s) dose rates using a 230 MeV superconducting synchrocyclotron proton pencil beam scanning (PBS) system. Two independent irradiation rounds were performed. Endpoints included 75-day survival, regenerating crypt counts, whole blood counts at day 4, and intestinal wall thickness, cyst-like structures, and cytokine levels at day 75. ResultsIn the first irradiation round, survival after 14.5 Gy FLASH was markedly improved (5/8 survivors) compared to CONV (0/8), whereas in the second round, survival rates were identical (2/7 per group). Overall, pooled data indicated improved survival with 14.5 Gy FLASH. The LD50 was 13.74 Gy in CONV and 14.48 Gy in FLASH mode, corresponding to a FLASH modifying factor of 0.95. FLASH at 14.5 Gy increased regenerating crypt numbers compared to CONV, but only in the first round, supporting survival outcomes. No significant differences were observed in whole blood counts, cytokine profiles, or long-term intestinal structural changes between groups. ConclusionFLASH proton therapy delivered with a clinical synchrocyclotron PBS system can reduce short-term gastrointestinal toxicity in mice. However, inconsistent results across irradiation rounds highlight limitations of this model for reliable FLASH studies.

cancer biology↗

bioRxiv2025

Autophagy maintains HEV identity and function during inflammation

High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary and tertiary lymphoid organs. They are uniquely equipped with high levels of peripheral node addressins (PNAd), harboring carbohydrate structures that serve as L-Selectin ligands to efficiently facilitate lymphocyte homing. During inflammation, the HEV network expands in SLOs, increasing lymphocyte infiltration, but the underlying mechanisms maintaining HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises LT{beta}R-signaling and the Unfolded Protein Response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LT{beta}R blockade impaired HEV function and reduced skin inflammation in psoriasis-bearing mice by limiting immune infiltration and cytokine release. Our work uncovers an unprecedented role of autophagy in safeguarding HEV identity and function during inflammation. HighlightsO_LIHigh endothelial venules (HEVs) exhibit heightened autophagy in comparison to non-HEV blood endothelial cells, which further increases during inflammation. C_LIO_LIAutophagy is pivotal in maintaining HEV fate and function, specifically during inflammation, via LT{beta}R signaling and the Unfolded Protein Response (UPR), ensuring the proper production of peripheral node addressins (PNAd) that serve as L-selectin ligands for the efficient influx of naive lymphocytes. C_LIO_LIBlocking autophagy in HEVs leads to disrupted PNAd production, HEV flattening and dedifferentiation, and reduced lymphocyte homing. C_LIO_LIGenetic and pharmacological perturbation of HEV function in the lymph nodes and skin lesions of psoriasis-bearing mice impaired neutrophil and lymphocyte recruitment, as well as cytokine secretion, thereby alleviating skin inflammation. C_LI

cell biology↗

bioRxiv2024

To what extent can life history strategies inform species conservation planning?

Global policy aims to prevent species extinctions; to support these aims conservation planners must effectively target interventions to reduce the extinction risk of species. However, there is often a lack of knowledge on the magnitude and direction of species responses to interventions and in turn the extent to which a species extinction risk is reduced. If we can use a species life history strategies to predict their responses to interventions, this offers a promising approach to better understand species extinction risks and conservation potential. Here we apply Dynamic Energy Budget Integral Project Models to 23 reptile species to investigate whether their life history traits can be summarised into a life history strategy framework using principal component analysis, and whether species positions along these axes predict their population growth rate, demographic resilience, sensitivity to perturbations and extinction risk. We found that species positions on reproductive and pace of life axes predicted reptile population growth rate and demographic resilience but not sensitivity to perturbations or extinction risk. Our findings show that reptile life history strategies can inform our understanding of reptile species conservation potential and could be applied to influence management decisions such as establishing monitoring timelines.

ecology↗

bioRxiv2024

Changing feeding levels reveal plasticity in elasmobranch life history strategies

Life history strategies are shaped by phylogeny, environmental conditions and individual energy budgets, and have implications for conservation biology. We summarised life history traits of 151 elasmobranch species into life history strategies for two contrasting feeding levels in a principal components analysis. Two axes, reproductive output and generation turnover, structure elasmobranch life history strategies, contrasting with results from similar studies. Species positions in this life history space were not fixed, but shifted to higher reproductive output when feeding level increased. We also found that both axes predicted population performance, but that population growth rate does not necessarily inform on a species demographic resilience. Finally, neither axis predicted IUCN conservation status. Our analyses reveal plasticity in species life history strategies and warn against extrapolating the life history strategy framework from one environment to another when predicting a species response to (climate) change, perturbations, and (over)exploitation.

ecology↗

bioRxiv2024

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the SCFA propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=109 HEIGHT=200 SRC="FIGDIR/small/603031v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c217b8org.highwire.dtl.DTLVardef@a340ceorg.highwire.dtl.DTLVardef@1f3c1d8org.highwire.dtl.DTLVardef@3b6fc9_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIGut microbiota-derived histamine activates enteric neurons via H3R C_LIO_LILocal intestinal H3R activation induces shift to homeostatic microglia in the spinal cord C_LIO_LICNS controlled decrease in endothelial leakiness resolves synovial inflammation C_LI

immunology↗

bioRxiv2023

In Vivo Tissue Distribution of Microplastics and Systemic Metabolomic Alterations After Gastrointestinal Exposure

Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. To investigate the impact of ingested MPs on target metabolomic pathways, mice were subjected to either polystyrene microspheres or a mixed plastics (5 {micro}m) exposure consisting of polystyrene, polyethylene and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid). Exposures were performed twice a week for four weeks at a dose of either 0, 2, or 4 mg/week via oral gastric gavage. Our findings demonstrate that, in mice, ingested MPs can pass through the gut barrier, be translocated through the systemic circulation, and accumulate in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolomic changes that occur in the colon, liver and brain which show differential responses that are dependent on dose and type of MPs exposure. Lastly, our study provides proof of concept for identifying metabolomic alterations associated with MPs exposure and adds insight into the potential health risks that mixed MPs contamination may pose to humans.

pharmacology and toxicology↗

bioRxiv2022

BRAFV600E expression in thyrocytes causes recruitment of immunosuppressive STABILIN-1 macrophages

Papillary thyroid carcinoma (PTC) is the most frequent histological subtype of thyroid cancers (TC), and BRAFV600E genetic alteration is found in 60% of this endocrine cancer. This oncogene is associated with poor prognosis, resistance to radioiodine therapy and tumor progression. Histological follow-up by anatomo-pathologists reveals that 2/3 of surgically-removed thyroids do not present malignant lesions. Continued fundamental research into the molecular mechanisms of TC downstream of BRAFV600E remains thus central to better understand the clinical behavior of these tumors. To study PTC, we used a mouse model in which expression of BRAFV600E is specifically switched on in thyrocytes by doxycycline administration. Upon daily intraperitoneal doxycycline injection, thyroid tissue rapidly acquired histological features mimicking human PTC. Transcriptomic analysis revealed major changes in immune signaling pathways upon BRAFV600E induction. Multiplex immunofluorescence confirmed the abundant recruitment of macrophages, among which a population of LYVE-1+/CD206+/STABILIN-1+ was dramatically increased. By genetically inactivating the gene coding for the scavenger receptor STABILIN-1, we showed an increase of CD8+ T cells in this in situ BRAFV600E dependent TC. Finally, we demonstrated the presence of CD206+/STABILIN-1+ macrophages in human thyroid pathologies. Altogether, we revealed the recruitment of immunosuppressive STABILIN-1 macrophages a PTC mouse model and the relevance of these observations in human thyroid tissues.

cancer biology↗

bioRxiv2019

Nicotinamide riboside augments the human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

NAD+ is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+ levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.

clinical trials↗

bioRxiv2017

Acetazolamide reduces exercise capacity following a five-day ascent to 4559 m on Monte Rosa

Acetazolamide (Az) is widely used to prevent and treat the symptoms of acute mountain sickness (AMS) but whether it alters exercise capacity at high altitude is unclear. Az (250 mg twice daily) or placebo were administered to 20 healthy adults (age range, 21-77 years) in a double-blind, randomized manner. Participants ascended over five days to 4559 m, before undertaking an incremental exercise test to exhaustion on a bicycle ergometer, with breath-by-breath gas measurements recorded using a portable gas analysis system. Maximum power output (Pmax) was reduced on Az compared with placebo (p=0.03), as was maximum O2 uptake (VO2max) (20.7 vs 24.6 mL/kg/min; p=0.06) and maximum expired CO2 (VCO2max) (23.4 vs 29.5 mL/kg/min; p=0.01). Comparing individuals matched for similar characteristics, Az-treated participants had smaller changes than placebo-treated participants in minute ventilation (88 vs 116 L/min: p=0.05), end tidal O2 (6.6 vs 9.3 mm Hg: p=0.009), end-tidal CO2 (-2.3 vs -4.2 mm Hg: p=0.005), VO2max (9.8 vs 13.8 mL/kg/min; p=0.04) and VCO2max (14.7 vs 20.8 mL/kg/min; p=0.009). There was a negative correlation between the mean ages of paired vs placebo-treated individuals and differences in Pmax reductions from base-line to altitude (r =-0.83: p<0.005) and HRmax at altitude (r=-0.71; p=0.01). Glomerular filtration rate (measured at sea-level) declined with increasing age (r=-0.69; p=0.001). Thus, 250mg of Az twice daily reduced exercise performance, particularly in older individuals. The age-related effects of Az may reflect higher tissue concentrations due to reduced drug clearance in older people.

physiology↗