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Commencing macrophage activity in prephagocytic multiple sclerosis tissue. Myelin appears to be intact, macrophages lack phagosomes, and there are some oligodendrocytes present with pyknotic nuclei (arrows) (Case 1, CD45, Â580).
Source publication
This study examined the roles of microglia and monocytes in myelin destruction in patients with early multiple sclerosis (MS). Twenty-two cases were studied; the clinical duration was <9 weeks in 10 cases. Twenty myeloid cell subtypes or categories were identified including 2 cell types not known previously to occur in demyelinating diseases. Comme...
Similar publications
The etiology of multiple sclerosis (MS), a demyelinating disease affecting the central nervous system (CNS), remains obscure. Although apoptosis of oligodendrocytes and neurons has been observed in MS lesions, the contribution of this cell death process to disease pathogenesis remains controversial. It is usually considered that MS-associated demye...
Citations
... 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). ...
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.
... Naive CD4 + T cells are the important responders in MS when antigen stimulates [33]. Monocytes implicate in the pathogenesis of MS by damaging myelin [41]. During the acute and relapsing phases of MS, B cells, CD4 + T cells and CD8 + T cells attack myelin, causing resultant demyelination [33,42,43]. ...
Background
The knowledge of normal‒appearing cortical gray matter (NAGM) in multiple sclerosis (MS) remains unclear. In this study, we aimed to identify diagnostic biomarkers and explore the immune infiltration characteristics of NAGM in MS through bioinformatic analysis and validation in vivo.
Methods
Differentially expressed genes (DEGs) were analyzed. Subsequently, the functional pathways of the DEGs were determined. After screening the overlapping DEGs of MS with two machine learning methods, the biomarkers’ efficacy and the expression levels of overlapping DEGs were calculated. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) identified the robust diagnostic biomarkers. Additionally, infiltrating immune cell populations were estimated and correlated with the biomarkers. Finally, the characteristics of immune infiltration of NAGM from MS were evaluated.
Results
A total of 98 DEGs were identified. They participated in sensory transduction of the olfactory system, synaptic signaling, and immune responses. Nine overlapping genes were screened by machine learning methods. After verified by ROC curve, four genes, namely HLA‒DRB1, RPS4Y1, EIF1AY and USP9Y, were screened as candidate biomarkers. The mRNA expression of RPS4Y1 and USP9Y was significantly lower in MS patients than that in the controls. They were selected as the robust diagnostic biomarkers for male MS patients. RPS4Y1 and USP9Y were both positively correlated with memory B cells. Moreover, naive CD4⁺ T cells and monocytes were increased in the NAGM of MS patients compared with those in controls.
Conclusions
Low expressed Y‒linked genes, RPS4Y1 and USP9Y, were identified as diagnostic biomarkers for MS in male patients. The inhomogeneity of immune cells in NAGM might exacerbate intricate interplay between the CNS and the immune system in the MS.
... HLA-DR + ramified microglia can accumulate and cluster in the NAWM forming small clusters of at least four up to 50 cells that are in contact with each other, which was described in relation to MS pathology for the first time in 1993 14,15 . These so-called microglia nodules are regularly considered to precede MS lesion formation [16][17][18][19][20][21][22][23][24] . They are found in early as well as advanced MS cases and persist throughout the disease course 25,26 . ...
Microglia nodules (HLA-DR⁺ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
... It is possible that dietary 23-OH UA has a similar effect in EAE mice, limiting the recruitment of monocyte-derived macrophages to sites of inflammation within the brain and restricting their disease contribution. MDM are considered the primary cell type involved in demyelination during EAE [33][34][35], suggesting that 23-OH UA's inhibitory effects on MDM recruitment may both dampen neuroinflammation and prevent demyelination at sites of MDM accumulation. ...
23-Hydroxy ursolic acid (23-OH UA) is a potent atheroprotective and anti-obesogenic phytochemical, with anti-inflammatory and inflammation-resolving properties. In this study, we examined whether dietary 23-OH UA protects mice against the acute onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Female C57BL/6 mice were fed either a defined low-calorie maintenance diet (MD) or an MD supplemented with 0.2% wgt/wgt 23-OH UA for 5 weeks prior to actively inducing EAE and during the 30 days post-immunization. We observed no difference in the onset of EAE between the groups of mice, but ataxia and EAE disease severity were suppressed by 52% and 48%, respectively, and disease incidence was reduced by over 49% in mice that received 23-OH UA in their diet. Furthermore, disease-associated weight loss was strikingly ameliorated in 23-OH UA-fed mice. ELISPOT analysis showed no significant differences in frequencies of T cells producing IL-17 or IFN-γ between 23-OH UA-fed mice and control mice, suggesting that 23-OH UA does not appear to regulate peripheral T cell responses. In summary, our findings in EAE mice strongly suggest that dietary 23-OH UA may represent an effective oral adjunct therapy for the prevention and treatment of relapsing–remitting MS.
... It is possible that dietary 23-OH UA has a similar effect in EAE mice, limiting the recruitment of monocyte-derived macrophages to sites of inflammation within the brain and restricting their disease contribution. MDM are considered the primary cell type involved in demyelination during EAE [18][19][20], suggesting that 23-OH UA's inhibitory effects on MDM recruitment may both dampen neuroinflammation and prevent demyelination at sites of MDM accumulation. ...
23-Hydroxy ursolic acid (23-OH UA) is a potent atheroprotective and anti-obesogenic phytochemical, with anti-inflammatory and inflammation resolving properties. In this study, we examined whether dietary 23-OH UA protects mice against the acute onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Female C57BL/6 mice were fed either a defined low-calorie maintenance diet (MD) or an MD supplemented with 0.2 % wgt/wgt 23-OH UA for 5 weeks prior to actively inducing EAE and during the 30 days post-immunization. We observed no difference in the onset of EAE between both groups of mice, but ataxia and EAE disease severity were suppressed by 52% and 48%, respectively, and disease incidence was reduced by over 49% in mice that received 23-OH UA in their diet. Furthermore, disease-associated weight loss was strikingly ameliorated in 23-OH UA-fed mice. ELISPOT analysis showed no significant differences in frequencies of T cells producing IL-17 or IFN- between 23-OH UA fed mice and control mice, suggesting that 23-OH UA does not appear to regulate peripheral T-cell responses. In summary, our findings demonstrate that dietary 23-OH UA may represent an effective oral adjunct therapy for the prevention and treatment of relapsing-remitting MS.
... Ma no ma, kad ðiø làs te liø ið ski ria mi ne nu sta ty ti tir pûs veiks niai, pa te kae á CNS, ga li tie sio giai ar ba ne tie sio giai su kel ti de mie li ni za cijà -per mik ro gli jos ak ty va ci jà ar in fil truo jan èius ið mo noci tø ki lu sius mak ro fa gus [19]. Pa þei di mo þi di niuo se yra ap tin ka mos mie li nà fa go ci tuo jan èios mak ro fa go ci ti nës làs te lës, ku rios, ma no ma, yra tie sio giai at sa kin gos uþ pa tolo gi nës de mie li ni za ci jos pro ce sà, ta èiau kol kas në ra tiksliai þi no ma, ar jos su si for muo ja ið CNS mik ro gli jos, ar ið per he ma to en ce fa li ná bar je rà pa te ku siø mo no ci tø [27]. ...
Multiple sclerosis is a chronic autoimmune disease of the central nervous system. Multiple sclerosis causes demyelination, impaired nervous system function, and eventually neurodegeneration. Microglia are cells of the central nervous system that develop from yolk sac macrophages during embryogenesis. These cells perform important functions in the development of the central nervous system and the retina, in the formation of synapses, protect against pathogens, and are involved in the removal of damaged structures. In response to environmental factors, microglia can acquire an inflammatory or anti-inflammatory phenotype. Microglia also play an important role in the pathogenesis of multiple sclerosis, and these cells are thought to be involved in both demyelination and remyelination processes. Microglial cells phagocytose harmful myelin remnants, promote remyelination, and control the proper response of peripheral immune cells, but disruption of these functions can lead to demyelination and neurodegeneration. Many of the disease-modifying drugs used to treat multiple sclerosis also affect microglial cells and inhibit their inflammatory response. Currently, new drugs are being researched that could be used to treat multiple sclerosis promoting the transition of microglia to an anti-inflammatory phenotype. The latest advanced cell therapy drugs have a broader spectrum of action – they inhibit inflammation, promote angiogenesis, perform trophic function, and inhibit oxidative damage.
... MS is the leading cause of neurologic disability in young adults, and available therapies are unable to stop neurological decline (1). The disease is characterized by the formation of demyelinating lesions containing abundant peripheral macrophages and CNS-derived microglia (2)(3)(4). These phagocytes display detrimental and beneficial functions in MS pathogenesis as they promote neuroinflammation, demyelination, and neurodegeneration, but also clear damaged myelin and produce neurotrophic factors, which facilitates remyelination (5,6). ...
A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of phagocytes that play a key role in lesion progression and remyelination, and therefore represent a promising therapeutic target in MS. We recently showed that unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell formation during demyelination. These fatty acids are elongated by the "elongation of very long chain fatty acids" proteins (ELOVLs), generating a series of functionally distinct lipids. Here, we show that the expression and activity of ELOVLs are altered in myelin-induced foam cells. Especially ELOVL6, an enzyme responsible for converting saturated and monounsaturated C16 fatty acids into C18 species, was found to be up-regulated in myelin phagocytosing phagocytes in vitro and in MS lesions. Depletion of Elovl6 induced a repair-promoting phagocyte phenotype through activation of the S1P/PPARγ pathway. Elovl6-deficient foamy macrophages showed enhanced ABCA1-mediated lipid efflux, increased production of neurotrophic factors, and reduced expression of inflammatory mediators. Moreover, our data show that ELOVL6 hampers CNS repair, as Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the mouse cuprizone model. These findings indicate that targeting ELOVL6 activity may be an effective strategy to stimulate CNS repair in MS and other neurodegenerative diseases.
... One region of normal-appearing white matter (NAWM), one active lesion, and one mixed active/inactive (chronic) lesion were selected in each MS patient sample (n = 4) for further immunohistopathological analysis ( Fig. 1A and S1). NAWM was mainly characterized by the presence of ramified microglia and the center of chronic lesions show typical presence of CD45 + myeloid cells, amoeboid and foamy microglia, as reported previously [26,27] (Fig. 1B and S2). The chronic rim predominantly consists of foamy microglia ( Fig. 1B and S2A). ...
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury. Here, we report that ferroptosis, an iron-catalyzed mode of regulated cell death (RCD), contributes to MS disease progression. Active and chronic MS lesions and cerebrospinal fluid (CSF) of MS patients revealed several signs of ferroptosis, reflected by the presence of elevated levels of (labile) iron, peroxidized phospholipids and lipid degradation products. Treatment with our candidate lead ferroptosis inhibitor, UAMC-3203, strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. In conclusion, the results identify ferroptosis as a detrimental and targetable factor in MS. These findings create novel treatment options for MS patients, along with current immunosuppressive strategies.
... The pathology of MS, described by Charcot as "sclerosed plaques," is accompanied by inflammatory lesions that cause demyelination and affect the pons, periventricular area, and spinal cord. ROS are responsible for the formation of lesions on glial cells and induce autoimmunity, leading to excessive recruitment of immune cells, including monocytes, T-lymphocytes, and plasma cells (Prineas and Parratt 2021). Studies indicate that immune cells infiltrate the myelin sheath of neurons, while ROS are believed to cause lipid oxidation within the myelin membrane, axons of neurons, and oligodendrocytes. ...
Aging accompanied by several age-related complications, is a multifaceted inevitable biological progression involving various genetic, environmental, and lifestyle factors. The major factor in this process is oxidative stress, caused by an abundance of reactive oxygen species (ROS) generated in the mitochondria and endoplasmic reticulum (ER). ROS and RNS pose a threat by disrupting signaling mechanisms and causing oxidative damage to cellular components. This oxidative stress affects both the ER and mitochondria, causing proteopathies (abnormal protein aggregation), initiation of unfolded protein response, mitochondrial dysfunction, abnormal cellular senescence, ultimately leading to inflammaging (chronic inflammation associated with aging) and, in rare cases, metastasis. RONS during oxidative stress dysregulate multiple metabolic pathways like NF-κB, MAPK, Nrf-2/Keap-1/ARE and PI3K/Akt which may lead to inappropriate cell death through apoptosis and necrosis. Inflammaging contributes to the development of inflammatory and degenerative diseases such as neurodegenerative diseases, diabetes, cardiovascular disease, chronic kidney disease, and retinopathy. The body’s antioxidant systems, sirtuins, autophagy, apoptosis, and biogenesis play a role in maintaining homeostasis, but they have limitations and cannot achieve an ideal state of balance. Certain interventions, such as calorie restriction, intermittent fasting, dietary habits, and regular exercise, have shown beneficial effects in counteracting the aging process. In addition, interventions like senotherapy (targeting senescent cells) and sirtuin-activating compounds (STACs) enhance autophagy and apoptosis for efficient removal of damaged oxidative products and organelles. Further, STACs enhance biogenesis for the regeneration of required organelles to maintain homeostasis. This review article explores the various aspects of oxidative damage, the associated complications, and potential strategies to mitigate these effects.
Graphical abstract
... Macrophages are antigen-presenting immune effector cells that are distributed throughout the body and play a key role in the pathogenesis of a number of chronic neuroinflammatory and neurodegenerative diseases, including MS, Parkinson's disease (PD), and Alzheimer's disease (AD) (Prineas and Parratt, 2021). Macrophages are classified as pro-inflammatory M1 type or anti-inflammatory M2 type based on their activating molecules, intracellular signaling molecules, surface markers, released cytokines, and cellular functions Zeng et al., 2022). ...
JOURNAL/nrgr/04.03/01300535-202403000-00044/inline-graphic1/v/2023-08-11T153926Z/r/image-tiff
Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system. Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis, a traditional experimental model of multiple sclerosis. This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis. We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type, as shown by reduced expression of inducible nitric oxide synthase/nitric oxide, interleukin-12, and CD16/32 and increased expression of arginase-1, interleukin-10, CD14, and CD206, which was linked to inhibition of Rho kinase activity, decreased expression of toll-like receptors, nuclear factor-κB, and components of the mitogen-activated protein kinase signaling pathway, and generation of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6. Crucially, Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis, resulting in later onset of disease, lower symptom scores, less weight loss, and reduced demyelination compared with unmodified macrophages. In addition, Fasudil-modified macrophages decreased interleukin-17 expression on CD4 ⁺ T cells and CD16/32, inducible nitric oxide synthase, and interleukin-12 expression on F4/80 ⁺ macrophages, as well as increasing interleukin-10 expression on CD4 ⁺ T cells and arginase-1, CD206, and interleukin-10 expression on F4/80 ⁺ macrophages, which improved immune regulation and reduced inflammation. These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response, thereby providing new insight into cell immunotherapy for multiple sclerosis.
