Biology subjects

Lemarchand, E.

Publications and source records attributed to Lemarchand, E..

3 recordsLinked to original sources

bioRxiv2025

Endothelial tPA-dependent recruitment of microglia to vessels protects the blood-brain barrier after stroke in mice

Thrombolysis with tissue-type plasminogen activator (tPA) remains the only pharmacological treatment for the acute phase of ischemic stroke. In this study, we hypothesize that endothelial tPA plays a key role in modulating the microglial response and maintaining blood brain barrier (BBB) integrity after stroke. Using a mouse model with conditional deletion for endothelial tPA (VeCadCre - tPAFlox) combined with a thrombotic stroke model and high-resolution imaging, we investigated the effects of endothelial tPA on vascular inflammation and microglia activation during the acute phase of stroke. Our results demonstrate that microglia-vessel contacts increase post-stroke. Notably, endothelial tPA deletion reduces vascular VCAM1 expression associated with decreased microglial activation and fewer microglia-vessel contacts. Following stroke, endothelial tPA deletion is associated with increased BBB permeability and heightened risk of haemorrhagic transformation. Collectively, these findings indicate that endothelial tPA mediates microglial recruitment to blood vessels, thereby exerting a protective effect on BBB integrity following ischemic stroke.

neuroscience↗

bioRxiv2024

Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke.

Inflammation is a key contributor to stroke pathogenesis and exacerbates brain damage leading to poor outcome. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. However, the distinct roles of the two major IL-1 receptor type 1 agonists, IL-1 and IL-1{beta}, and the specific role of IL-1 in ischemic stroke remain largely unknown. Here we show that IL-1 and IL-1{beta} have different spatio-temporal expression profiles in the brain after experimental stroke, with early microglial IL-1 expression (4 h) and delayed IL-1{beta} expression in infiltrated neutrophils and a small microglial subset (24-72 h). We examined for the first time the specific role of microglial-derived IL-1 in experimental permanent and transient ischemic stroke through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1 deletion did not influence acute brain damage, cerebral blood flow, IL-1{beta} expression, neutrophil infiltration, microglial nor endothelial activation after ischemic stroke. However, microglial IL-1 knock out (KO) mice showed reduced peri-infarct vessel density and reactive astrogliosis at 14 days post-stroke, alongside long-term impaired functional recovery. Our study identifies for the first time a critical role for microglial IL-1 on neurorepair and functional recovery after stroke, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop more effective therapies.

neuroscience↗

bioRxiv2021

Itaconate and fumarate derivatives exert a dual inhibitory effect on canonical NLRP3 activation in macrophages and microglia

The NLRP3 inflammasome is a multi-protein complex that regulates the protease caspase-1 and subsequent interleukin (IL)-1{beta} release from cells of the innate immune system, or microglia in the brain, in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4-octyl itaconate (4OI) and dimethyl fumarate (DMF), limit both expression of IL-1{beta}, and IL-1{beta} release following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses in macrophages and microglia require further investigation. Using murine bone marrow-derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI and 4OI pre-treatment limited IL-1{beta}, IL-6 and tumor necrosis factor production in response to lipopolysaccharide (LPS) priming, as well as inhibiting subsequent NLRP3 inflammasome activation. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS-primed macrophages, mixed glia and OHSCs, including ASC speck formation, caspase-1 activation, gasdermin D cleavage and IL-1{beta} release. Finally, DMF, an approved treatment for multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to the phospholipid lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism of action for DMF in multiple sclerosis through NLRP3 inhibition. Together, these findings reveal the importance of immunometabolic regulation for both the priming and activation steps of NLRP3 activation in macrophages and microglia. Furthermore, we highlight itaconate and fumarate derivatives as a potential therapeutic option in NLRP3-driven diseases, including in the brain. Summary statementWe show that itaconate and fumarate derivatives inhibit both the priming and activation steps of NLRP3 inflammasome responses in macrophages and microglia, revealing the importance of immunometabolic NLRP3 regulation.

immunology↗