Biology subjects

Manoury, B.

Publications and source records attributed to Manoury, B..

4 recordsLinked to original sources

bioRxiv2026

Toll-like receptor 9 contributes in microglial activation and lysosomal dysfunction to promote Alzheimer disease

Toll like receptor 9 (TLR9) is an endosomal-lysosomal innate immune receptor which recognizes microbial and host-derived double-stranded DNA (dsDNA) to induce cellular immunity. TLR9 pathway has been implicated in Alzheimers disease (AD) pathology via its ability to modulate peripheral immune cells but its exact role in the central nervous system (CNS) remains unclear. Here we show that extranuclear dsDNA accumulating in human AD brain and in a mouse model of AD, together with microglia around amyloid-{beta} (A{beta}) plaques stimulates TLR9 in vitro. Loss of TLR9 inhibits the transition of homeostatic microglia to reactive microglia, a cell type associated with a chronic pro-inflammatory state, promoting their reprogramming into an anti-inflammatory state, thereby restoring lysosomal integrity required for A{beta} peptides degradation. Predisposition to lysosome permeabilization could be mimicked with repeated TLR9 stimulation using CpG-A ODNs in a human microglial cell line and was rescued with TLR9 inhibition. Furthermore, lack of TLR9 protects mice developing AD from cognitive defects and neuronal loss. A{beta} pathology is also reduced specifically in male mice. Altogether, our results have identified a critical role of TLR9 in AD, where it modulates microglial activation and lysosome function to interfere with the progression of AD. These findings suggest that targeting TLR9 signaling and lysosomal function may be a relevant strategic approach to reduce AD pathology.

immunology↗

bioRxiv2025

PI3Kδ Bridges Microbial Surveillance with Antigen Presentation to Reinforce Intestinal Immunity

Phosphoinositide 3-kinase delta (PI3K{delta}) is essential for immune cell functions, preventing immunodeficiency and inflammation; however, its role in dendritic cell (DC)-mediated immune regulation remains unknown. Here, we report a key role for DC-intrinsic PI3K{delta} in linking microbial recognition with antigen presentation for effective T-cell priming. Using genetic and functional assays, we demonstrate that PI3K{delta} deficiency in DCs leads to broad dysregulation of intestinal CD4 T-cell immunity, characterized by impaired regulatory T-cell expansion and increased susceptibility to colitis. DC-based studies show that PI3K{delta} links pattern-recognition-receptor signaling to MHC class I- and II-restricted presentation of phagosome-associated antigens by facilitating NOX2-dependent oxidative burst through RAC2, while mitigating inflammasome activation. In contrast, PI3K{delta} deficiency disrupts phagosomal pH balance, leading to accelerated acidification and proteolysis of antigens, impairing T-cell activation. Our study identifies PI3K{delta} as a key coordinator of phagosome dynamics, important for DC adaptive programming that shapes T-cell responses and supports intestinal immune homeostasis.

immunology↗

bioRxiv2022

Microglial P2X4 receptors promote ApoE degradation and cognitive deficits in Alzheimer disease

Numerous evidence support that microglia contributes to the progression of Alzheimers disease. P2X4 receptors are ATP-gated channels, which are de novo expressed in a subset of reactive microglia associated to various pathological contexts, contributing to microglial functions. Here, we investigated the role of P2X4 in the context of Alzheimer disease (AD). In both human AD brain and APPswe/PSEN1dE9 mice, P2X4 is almost exclusively expressed in plaque associated microglia. Genetic deletion of P2rx4 results in the reversal of cognitive declines and in a lower amount of soluble A{beta}1 -42 in 12 months old APP/PS1 mice, while no obvious alteration of plaque associated microglia characteristics is observed. Using proteomic, we identified ApoE as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B activity promoting ApoE degradation; P2rx4 deletion results in higher amount of intracellular and secreted ApoE in both BMDM and microglia from APP/PS1 brain. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering A{beta} peptide clearance, which in turn might promote synaptic dysfunctions and cognitive deficits. Our findings also uncover a specific interplay between purinergic signaling, microglial ApoE, sA{beta} species and cognitive deficits associated with AD.

neuroscience↗

bioRxiv2021

The Autophagy Receptor TAX1BP1 (T6BP) is a novel player in antigen presentation by MHC-II molecules.

CD4+ T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented on the surface of antigen presenting cells (APCs) by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces the mislocalization of the MHC-II-loading compartments and a rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. We determined the interactome of T6BP, identified calnexin as a T6BP partner and show that CANX cytosolic tail is required for this interaction. Remarkably, calnexin silencing replicates the functional consequences of T6BP silencing: decreased CD4+ T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway and we propose one potential mechanism of action.

immunology↗