Biology subjects

Engelenburg, H. J.

Publications and source records attributed to Engelenburg, H. J..

4 recordsLinked to original sources

bioRxiv2025

Mapping Leukocyte Dynamics during Neuroinflammation Identifies Meningeal Monocyte-Derived Macrophages as Drivers of Progressive Disease

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by increasing disability. The cellular and molecular drivers of clinical transition towards progressive disease are poorly understood. Here, we combine single-cell profiling technologies with genetic and pharmacological perturbations across the course of murine CNS inflammation to dissect the role of the local immune landscape in disease progression. We uncover a chronic monocyte-to-phagocyte transition as a hallmark of progressive disease, characterized by the emergence of maladaptive, lipid-associated macrophages (LAMs) marked by lysosomal activation and fibrotic features. Spatial transcriptomics and multiplexed imaging revealed that these LAMs localized to the leptomeninges in close proximity to parenchymal colony-stimulating factor (CSF)-1 producing disease-associated microglia (DAMs) and meningeal granulocyte-macrophage (GM)-CSF-expressing T helper cells that license their differentiation. Interference with this local cytokine network revealed a protective role for resident microglia and implicated monocyte-derived phagocytes as key drivers of progressive neuroinflammation. Notably, LAM-like macrophages could also be identified in the meninges of people with MS, indicating a homology to human disease. By elucidating their ontogeny, spatial niche, and regulatory cytokine milieu, we provide a mechanistic framework for targeting harmful myeloid states while preserving reparative CNS immunity in progressive MS.

immunology↗

bioRxiv2024

Foamy microglia link oxylipins to disease progression in multiple sclerosis

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by expanding demyelinating lesions, leading to severe and irreversible disability. The mechanisms driving lesion expansion, however, remain poorly understood. Here, using a multi-omics approach, we identified foamy microglia as primary contributors to the molecular profile of lesions and disease progression in secondary progressive MS. Lesions with foamy microglia are marked by the accumulation of cholesterol esters, bismonoacylglycerolphosphates (BMP), and oxylipins, along with high B-cell infiltration, increased levels of immunoglobulin G1, and elevated expression of Fc{gamma}- and complement receptors. Lesions with foamy GPNMB+-microglia display markers of enhanced phagocytosis, lipid metabolism, lysosomal dysfunction, and antigen presentation, but lack classical pro-inflammatory markers. Our data suggest that sustained phagocytosis of myelin overwhelms microglial endo-lysosomal capacity, leading to lipid droplet and oxylipin formation. This microglial phenotype may induce further recruitment of adaptive immune cells, axonal damage, drive lesion expansion and prevent remyelination. Monoacylglycerol lipase, involved in producing oxylipin precursors, was identified as a potential therapeutic target to disrupt this cycle and prevent chronic lesion expansion.

neuroscience↗

bioRxiv2024

CD4+ Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Therapeutic options against multiple sclerosis (MS) preventing T cell migration to the central nervous system (CNS) have remarkable clinical effects against the relapsing-remitting (RRMS) form of the disease, while they are poorly effective against its progressive form (PMS). Disability progression in PMS is thought to result from an interplay between smoldering local inflammation and neurodegeneration. We postulated that an ongoing inflammatory process mediated by CNS-resident memory CD4+ T cells (CD4+ Trm) could contribute to promote disease chronicity independently of de novo recruitment of peripheral autoreactive T cells. Indeed, our results revealed the presence of bona fide CD4+ Trm expressing CD69, CXCR6, P2RX7, CD49a and the transcription factor Hobit in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in the brain of persons with PMS. Single-cell transcriptional analysis uncovered their transcriptional heterogeneity and inflammatory potential and, accordingly, CD4+ Trm preferentially localized within inflammatory lesions. Finally, depletion of both the recirculating and the CNS-resident CD4+ T cell compartments was required to alleviate neurological signs during the chronic phase of EAE. Our results, therefore, indicate that CD4+ Trm actively contribute to maintain a chronic inflammatory state in the CNS, promoting damage and/or preventing repair, and suggest that new therapeutic strategies for the treatment of PMS should consider targeting the CNS-resident T cell compartment.

immunology↗

bioRxiv2022

Molecular underpinnings of programming by early-life stress and the protective effects of early dietary ω6/ω3 ratio, basally and in response to LPS: hippocampal mRNA-miRNAs integrated approach

Early-life stress (ELS) exposure increases the risk for mental disorders, including cognitive impairments later in life. We have previously demonstrated that a dietary low {omega}6/{omega}3 polyunsaturated fatty acid (PUFA) ratio protects against ELS-induced cognitive impairments. Several studies have implicated the neuroimmune system in the ELS and diet mediated effects, but currently the molecular pathways via which ELS and early diet exert their long-term impact are not yet fully understood. Here we study the effects of ELS and dietary PUFA ratio on hippocampal mRNA and miRNA expression in adulthood, both under basal and inflammatory conditions. Male mice were exposed to chronic ELS by the limiting bedding and nesting material paradigm from postnatal day(P)2 to P9, and provided with a diet containing a high (15:1.1) or low (1.1:1) {omega}6 linoleic acid to {omega}3 alpha-linolenic acid ratio from P2 to P42. At P120, memory was assessed using the object location task. Subsequently, a single lipopolysaccharide (LPS) injection was given and 24 hours later hippocampal genome-wide mRNA and microRNA (miRNA) expression was measured using microarray. An integrated miRNA - mRNA analysis revealed that ELS and early diet induced miRNA driven mRNA expression changes into adulthood. Under basal conditions both ELS and the diet affected molecular pathways related to hippocampal plasticity, with a low {omega}6/{omega}3 ratio diet specific activation of molecular pathways associated with improved hippocampal plasticity and learning and memory in mice previously exposed to ELS (e.g., CREB signaling and endocannabinoid neuronal synapse pathway). LPS induced miRNA and mRNA expression was strongly influenced by both ELS and early diet. In mice fed the high {omega}6/{omega}3 diet, LPS increased miRNA expression leading to activation of inflammatory pathways. In contrast, in mice fed the low {omega}6/{omega}3 diet, LPS reduced miRNA expression and altered target mRNA expression ultimately leading to limited activation of inflammatory signaling pathways and inhibition of pathways associated with hippocampal plasticity which was especially apparent in mice previously exposed to ELS. This data provides molecular insights into how the low {omega}6/{omega}3 diet during development could exert its long-lasting beneficial effects on hippocampal plasticity and learning and memory especially in a vulnerable population exposed to stress early in life, providing the basis for the development of intervention strategies.

neuroscience↗