Targeting lipophagy in macrophages improves repair in multiple sclerosis

Haidar, Mansour; Loix, Melanie; Vanherle, Sam; Dierckx, Tess; Vangansewinkel, Tim; Gervois, Pascal; Wolfs, Esther; Lambrichts, Ivo; Bogie, Jeroen F. J.; Hendriks, Jerome J. A.

doi:10.1080/15548627.2022.2047343

Cited by 26 publications

(14 citation statements)

References 62 publications

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“…Additionally, the upregulation of pathways related to Antigen presentation, Interferon signaling , and Interleukin-2 signaling underscores the involvement of immune regulatory mechanisms in the pathogenesis, hinting at potential autoimmune components in MS [16]. Moreover, Lipophagy and Endosomal/vacuolar pathways point towards potential disruptions in cellular metabolism and intracellular trafficking processes [17]. The heightened activity in pathways associated with DNA damage response and senescence , as well as regulation of Heat shock response , suggests potential cellular stress and adaptive responses [18].…”

Section: Discussionmentioning

confidence: 99%

Comparing Single-Cell Transcriptomes of Blood and Cerebrospinal Fluid Leukocytes in Multiple Sclerosis

Sayad,

Hiatt,

Mustafa

2024

Preprint

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Background. Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system, marked by inflammation, demyelination, and neurodegeneration. Diagnosis is complex due to overlapping symptoms with other neurological conditions, typically relying on clinical evaluation, neurological exams, and tests like magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. Recent advances in technology, particularly single-cell analysis of blood and CSF leukocytes, hold promise for enhancing MS diagnosis by providing insights into immune cell involvement at a molecular level, potentially enabling more precise diagnostics and personalized treatments. Method. We acquired single-cell RNA Sequence (RNA-Seq) data (GSE138266) from the website of the National Institutes of Health of the United States (NIH), comprising blood and CSF samples from patients diagnosed with idiopathic intracranial hypertension (IIH) and MS. Our analysis focused on identifying genes, pathways and gene ontology terms with distinct expression patterns in MS compared to IIH. Results. We identified clear differences in gene expression profiles between blood and CSF samples in MS, contrasting with single-cell leukocyte samples from IIH. The increased expression of genes in MS suggests a boost in immune activity and regulation of cellular proliferation, while decreased expression points to disruptions across various functional categories. Gene ontology analysis identifies upregulated terms associated with cellular differentiation, apoptotic regulation, and immune responses in MS, while downregulated terms suggest disruptions in cellular signaling cascades and myelination processes. Similarly, Reactome pathway analysis unveils upregulated pathways in MS related to cell cycle regulation and immune mechanisms, contrasting with downregulated pathways indicative of disruptions in oxygen transport and cellular metabolism. Conclusion. Our study offers a thorough examination of single-cell transcriptomic data, unveiling unique gene expression patterns, gene ontology terms, and Reactome pathways linked to MS pathophysiology. Notably, our findings identify CD69 and HNRNPK as potential key genes driving MS progression. By clarifying molecular differences between MS and IIH, our findings enhances our grasp of MS pathogenesis and unveils promising targets for diagnostic and therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Comparing Single-Cell Transcriptomes of Blood and Cerebrospinal Fluid Leukocytes in Multiple Sclerosis

Sayad,

Hiatt,

Mustafa

2024

Preprint

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“…However, as the disease progresses, there is a shift toward M2-type macrophages taking over ( 47 , 49 ) ( Figure 3 ). It is known that taking myelin reduces inflammation and encourages the development of anti-inflammatory macrophages, demyelination is a significant inflammatory component of MS and EAE, and macrophages have a direct impact on it by removing myelin from the myelin sheath by phagocytosis ( 50 , 51 ). Additionally, the blood-brain barrier’s (BBB) destruction is a significant contributor to neurological diseases, BBB can block the entry of harmful compounds into the CNS under normal physiological circumstances, whereas immune cells can pass through BBB ( 52 ).…”

Section: Autoimmune Diseasementioning

confidence: 99%

Macrophage polarization: an important role in inflammatory diseases

Luo,

Zhao,

Cheng

et al. 2024

Front. Immunol.

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Macrophages are crucial cells in the human body’s innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis in vivo. M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.

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“…Additionally, the disease-mediated peroxisome injury in BAMs, leading to demyelination and axonal loss, may be prevented through treatment with 4-Phenylbutyrate, which serves as a potential therapeutic approach for halting inflammatory demyelination and the progression of MS [113]. Lastly, foamy macrophages are formed in brain regions during MS; by targeting lipophagy, remyelination can be promoted as some BAM subtypes may be involved in the aforementioned process [114,115].…”

Section: Bams In Multiple Sclerosismentioning

confidence: 99%

CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease

Dermitzakis,

Theotokis,

Evangelidis

et al. 2023

CIMB

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Being immune privileged, the central nervous system (CNS) is constituted by unique parenchymal and non-parenchymal tissue-resident macrophages, namely, microglia and border-associated macrophages (BAMs), respectively. BAMs are found in the choroid plexus, meningeal and perivascular spaces, playing critical roles in maintaining CNS homeostasis while being phenotypically and functionally distinct from microglial cells. Although the ontogeny of microglia has been largely determined, BAMs need comparable scrutiny as they have been recently discovered and have not been thoroughly explored. Newly developed techniques have transformed our understanding of BAMs, revealing their cellular heterogeneity and diversity. Recent data showed that BAMs also originate from yolk sac progenitors instead of bone marrow-derived monocytes, highlighting the absolute need to further investigate their repopulation pattern in adult CNS. Shedding light on the molecular cues and drivers orchestrating BAM generation is essential for delineating their cellular identity. BAMs are receiving more attention since they are gradually incorporated into neurodegenerative and neuroinflammatory disease evaluations. The present review provides insights towards the current understanding regarding the ontogeny of BAMs and their involvement in CNS diseases, paving their way into targeted therapeutic strategies and precision medicine.

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Targeting lipophagy in macrophages improves repair in multiple sclerosis

Cited by 26 publications

References 62 publications

Comparing Single-Cell Transcriptomes of Blood and Cerebrospinal Fluid Leukocytes in Multiple Sclerosis

Comparing Single-Cell Transcriptomes of Blood and Cerebrospinal Fluid Leukocytes in Multiple Sclerosis

Macrophage polarization: an important role in inflammatory diseases

CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease

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