BTK inhibition prevents microglia-mediated demyelination induced by multiple sclerosis patient antibodies
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE330704 | GEO | 2026/08/31
REPOSITORIES: GEO
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Project description:Bruton’s tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B cell and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, inhibitors of BTK have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain penetrant small molecule BTK inhibitors may also help to address compartmentalized neuroinflammation which is proposed to underlie MS disease progression. BTK is expressed by microglia, the resident innate immune cells of the brain, however the precise roles of microglial BTK and the impact of BTK inhibitors on microglial functions is still being elucidated. Much research to date has also focused on the effects of BTK inhibitors using rodent disease models. Here we characterize the pharmacological and functional properties of fenebrutinib (FEN), a potent, highly selective, noncovalent, reversible BTK inhibitor, in human microglia and complex human brain cell systems including brain organoids. We find that FEN blocks the effects of microglial FcγR activation including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by FEN treatment. In contrast, FEN had no significant impact on human microglial pathways linked to TLR4 or NLRP3 signaling nor myelin phagocytosis. Our study increases the understanding of BTK functions in human microglial signaling relevant to MS pathogenesis and suggests that FEN could attenuate detrimental microglial activity associated with FcγR activation in MS patients.
2024-10-28 | GSE276803 | GEO
Project description:Microglia, the resident immune cells of the central nervous system (CNS), are important regulators of normal brain activities. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Based on the observation of diminished Dicer positive microglia/macrophages number in demyelinating white matter lesions (WMLs) of human MS brains, here we probed the impact of impaired microRNA (miRNA)-mediated post-transcriptional gene regulation in a mouse model lacking microglia/macrophage-specific Dicer1 expression during demyelination and remyelination. Conditional Dicer1 ablation and loss of miRNAs expression in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting oligodendrocyte progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer1-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, finding from this study highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination.
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Project description:Multiple sclerosis (MS) is a chronic, inflammatory condition characterized by demyelination and neurodegeneration. Regeneration of lost myelin, or remyelination, occurs in people with MS but is prone to failure and impaired with age. Remyelination is facilitated by microglia but our understanding of the microglial response during remyelination is incomplete. Here, we profiled the microglial response in the lysolecithin mouse model of remyelination using single-cell RNA sequencing. We found several distinct microglial states during the early stages of remyelination that coalesced into a resolved microglial state defined by myelin transcripts. This resolved state was also present in MS brains. As remyelination becomes inefficient with age, we profiled microglia from both young and middle-aged mice during remyelination and found a delay in several microglial states, in concordance with delayed remyelination. Overall, microglia synchronously initiate a multi-faceted response during efficient remyelination in young mice, which becomes dysregulated with age.
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Project description:We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor found on microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases and analyzed the impact of the antibody on myelination and gene expression in single cells. We found that blocking TREM2 depleted a specific population of microglia characterized by high expression of the transcription factor MAFB during remyelination. These MAFB-high microglia were crucial for myelin repair, and their depletion led to impairment of myelinating oligodendrocytes. Importantly, we identified MAFB+ microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that are critical for myelin repair. This finding has important implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a potential therapeutic strategy.
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Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Brain lysate of adult WT, USP18ko, IFNAR1ko and USP18ko:IFNARko mice were analyzed
2015-04-20 | E-GEOD-61499 | biostudies-arrayexpress
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Primary microglia (WT, USP18ko and USP18_C61A mice) and BV-2 cells (treated with control siRNA or siRNA against USP18) were incubated with 500 U/ml IFN-b. At different timepoints (0h, 6h, and 24h) RNA samples were taken and analyzed via Microarray
2015-04-20 | E-GEOD-61500 | biostudies-arrayexpress
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
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Project description:Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris, which is released from the damaged myelin sheaths during demyelination, can act as an inflammatory stimulus to promote sterile inflammation and neurological pathologies, but the mechanism is poorly understood. Here, we show that lysophosphatidylserine (LysoPS)-GPR34 axis plays a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia to produce IL-1and IL-6 via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, LysoPS production and GPR34 signaling were found to be essential for neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Importantly, pharmacologic blockade of GPR34 showed potential therapeutic effects on these disease models. Thus, our results identify GPR34 as a key receptor to sense myelin debris and promote neuroinflammation, and suggest it as a potential target for demyelination-associated diseases.
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Project description:Failure in remyelination is a key feature of progressive multiple sclerosis (MS) that drive neurodegeneration and accumulation of disabilities. Microglia crucially facilitate oligodendrocyte remyelination in MS lesions through myelin phagocytosis, and subsequent cholesterol metabolism and release. However, microglia lose this capacity in chronic demyelinated lesions, as they acquire a dysfunctional phenotype characterized by intracellular accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Given the abundance of microglia in chronic MS lesions, revitalizing their pro-remyelination capacity represents a critical repair strategy for progressive MS. Here, we reveal that dysregulation of neuregulin-1 underlies impaired remyelination in chronically demyelinated brain lesions. Therapeutic restoration of neuregulin-1 supports remarkable myelin regeneration by augmenting microglia capacity for clearance of myelin debris, cholesterol metabolism and efflux. Altogether, we demonstrate the promise of neuregulin-1 as an endogenous target to facilitate microglia reparative functions in progressive MS in which there is an unmet critical need for new treatments.
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Project description:In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1, and ANO4. Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16, and OLR1, and lipid uptake, such as CHIT1, GPNMB, and CCL18. Except CCL18, these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.
2018-01-01 | GSE108000 | GEO