Figure - available from: Frontiers in Immunology
This content is subject to copyright.
Anti-OPN autoantibodies (autoAbs) are increased in relapsing–remitting (RR) patients compared with secondary-progressive (SP) and primary-progressive (PP) patients and healthy controls (HCs). (A) AutoAbs to osteopontin (OPN) in multiple sclerosis (MS) patients and HCs. AutoAbs detected by ELISA using OPN full-length as the capture protein. In the left panel, black triangles mark MS patients and white triangles the HCs. In the right panel, patients are stratified according to their clinical form at the time of blood withdrawal. Dark gray triangles: RR-relapse MS patients; light gray triangles: RR-remission MS patients; gray circles: SP-MS patients; gray diamonds: PP-MS patients; boxes: interquartile range with medians. p Values were calculated with the Mann–Whitney U-test. The horizontal lines indicate the 75th (dashed line) and 95th (continuous line) percentiles of the HCs. (B) Inverse correlation between autoAbs to OPN and disease duration in RR patients (Pearson correlation test) (*p < 0.01, **p < 0.001, ***p < 0.0001).
Source publication
Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antib...
Similar publications
Objective:
Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing...
Gelatinase B/matrix metalloproteinase-9 (MMP-9) triggers multiple sclerosis (MS) and the animal model of experimental autoimmune encephalomyelitis (EAE) by the breakdown of the blood-brain barrier. Interestingly, MMP-9 is beneficial in systemic autoimmunity caused by Fas-deficiency. Fas-deficient (faslpr) and Fas-ligand-deficient mice are protected...
Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis and insulin signaling, respectively, the role for Akt3 remains uncertain. Akt3 is predominantly expressed in the brain, and total deletion of Akt3 in mice results in a reduction in br...
Significance
B cell depletion via anti-CD20 monoclonal antibodies is a novel, highly efficient therapy for multiple sclerosis (MS). In a murine MS model, we investigated three mechanistic questions that cannot be addressed in humans. First, we established that a fraction of mature B cells in the spleen is resistant to anti-CD20. Second, we determin...
Objective: To investigate the imaging and biodistribution of a novel zirconium-89 (⁸⁹Zr)-labeled mouse anti-cd20 monoclonal antibody (mAb) in control and experimental autoimmune encephalomyelitis (EAE) mice following subcutaneous (s. c.) and intravenous (i.v.) administration.
Background: Anti-cd20-mediated B-cell depletion using mAbs is a promising...
Citations
... The level of OPN, an extracellular matrix protein, was reportedly elevated in the serum of an EAE animal model [12]; it was also secreted from macrophages and some glial cells in the CNS tissues of EAE animal models [13]. Because OPN was associated with increased vascular permeability in the diabetic retina [14], increased serum OPN levels in EAE animal models would nonspecifically accelerate inflammatory cell migration in various tissues, including the lungs, leading to inflammatory cell infiltration. ...
Importance:
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis characterized by inflammation within the central nervous system. However, inflammation in non-neuronal tissues, including the lungs, has not been fully evaluated.
Objective:
This study evaluated the inflammatory response in lungs of EAE mice by immunohistochemistry and histochemistry.
Methods:
Eight adult C57BL/6 mice were injected with myelin oligodendrocyte glycoprotein35-55 to induce the EAE. Lungs and spinal cords were sampled from the experimental mice at the time of sacrifice and used for the western blotting, histochemistry, and immunohistochemistry.
Results:
Histopathological examination revealed inflammatory lesions in the lungs of EAE mice, characterized by infiltration of myeloperoxidase (MPO)- and galectin-3-positive cells, as determined by immunohistochemistry. Increased numbers of collagen fibers in the lungs of EAE mice were confirmed by histopathological analysis. Western blotting revealed significantly elevated level of osteopontin (OPN), cluster of differentiation 44 (CD44), MPO and galectin-3 in the lungs of EAE mice compared with normal controls (p < 0.05). Immunohistochemical analysis revealed both OPN and CD44 in ionized calcium-binding adapter molecule 1-positive macrophages within the lungs of EAE mice.
Conclusions and relevance:
Taken together, these findings suggest that the increased OPN level in lungs of EAE mice led to inflammation; concurrent increases in proinflammatory factors (OPN and galectin-3) caused pulmonary impairment.
... In physiological contexts, OPN contributes significantly to tissue maintenance, wound healing, immune system regulation, and stress response mechanisms [9]. However, its involvement extends to the pathogenesis of several conditions, including atherosclerosis [10], cancer [11], autoimmune disorders [12], chronic inflammation [13], and sepsis [14]. OPN additionally functions as a diagnostic and prognostic biomarker for these disorders [15][16][17]. ...
Osteopontin (OPN), a multifunctional protein, has emerged as a fascinating subject of study due to its diverse roles in various physiological and pathological processes [...]
... On the other hand, OPN, an essential bone-remodeling-associated protein, mainly promotes T-cell, macrophage, dendritic cell, and B-cell activation, and subsequently modifies T-cell-mediated and B-cell-mediated immunity. Either imbalanced BAFF or OPN can escape immune tolerance and result in AID development [45][46][47][48][49][50]. Moreover, in our recent publications, we demonstrated that serum BAFF and OPN levels were upregulated in GD, were associated with TSHRAb and thyroid function, and suggested that both BAFF and OPN could exhibit remarkable roles in inducing GD and modulating disease progression [51,52]. ...
Background
Autoimmune thyroid disease (AITD) can cause enormous health burdens; however, trustworthy biomarkers in identifying the onset and progression of AITD are limited. In this study, we attempted to discover new potential serum biomarkers to discriminate AITD using mass spectrometry (MS).
Methods
In the biomarker study cohort, 20 patients with Graves’ disease (GD), 20 patients with Hashimoto’s thyroiditis (HT), and 20 healthy controls were enrolled for a liquid chromatographic-tandem MS assessment. A novel biomarker, keratin 1 (KRT1), was selected for further evaluation in the validation cohort, including 125 patients with GD, 34 patients with HT, and 77 controls. Relationships of serum KRT1 with AITD-related immunomodulatory cytokines were also analyzed using enzyme-linked immunosorbent assays (ELISAs).
Results
In the MS analysis, KRT1 was the single marker overexpressed in GD, while it was underexpressed in HT. In the ELISA analysis of the validation cohort, KRT1 was consistently upregulated in GD, while it was not downregulated in HT. There were significant associations of KRT1 levels with thyroid function in GD, AITD, and overall subjects. Additionally, a significant association of KRT1 levels with thyroid-stimulating hormone receptor antibody (TSHRAb) levels was observed. Moreover, there were significant associations of KRT1 with osteopontin (OPN) and B-cell activating factor (BAFF) levels in GD.
Conclusions
Serum KRT1 levels were upregulated in GD and were associated with thyroid function and TSHRAb levels. Moreover, KRT1 was correlated with the BAFF and OPN levels in GD patients. Further molecular-based research to elucidate the role of KRT1 in the pathogenesis of AITD is needed.
... It corresponds with the reports showing that OPN stimulates IL-17A production in EAE [21]. Vaccination with OPN inducing anti-OPN antibodies during EAE decreased disease severity and this effect was correlated with decreased secretion of IL-17 by T cells [5]. OPN can promote relapses of SM/EAE by providing a survival signal to autoreactive T cells and may be a critical factor which influences the transition from relapsing remitting to secondary progressive demyelinating disease [31]. ...
Introduction:
Osteopontin (OPN) is involved in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). The aim of this study was to investigate the expression of OPN in spinal cords of mice in the successive phases of EAE, to compare it with the density of inflammatory cells, oligodendrocytes and with the expression of interleukin (IL)-17A and to assess the effect of anti-α4β1 integrin (VLA-4) treatment.
Material and methods:
Experimental autoimmune encephalomyelitis (EAE) mice were injected with anti-VLA-4 antibodies or, as treatment control, with immunoglobulin G (IgG). Spinal cords were sectioned and immunostained for OPN, CD45 (overall leukocytes), CD3 (T cells), Iba1 (activated macrophages/microglia), IL-17A, and CNP1 (oligodendrocytes). Microscopic images were analysed and the percentage of immunopositive areas encompassing the whole spinal cord cross-sectional area were assessed in images for each antigen.
Results:
Osteopontin was expressed by inflammatory cells and by a minority of neurons and blood vessels. Most of the studied parameters followed the temporal pattern of clinical scores: increase in the peak phase and decrease in the chronic phase. Only OPN and IL-17A remained at a high level in the chronic phase, while CNP1 expression gradually decreased in the successive phases. Anti-VLA-4 treatment lowered the expression of the studied antigens in the peak and chronic phases with the exception of oligodendrocyte marker CNP1 which in both phases showed an increased expression.
Conclusions:
Involvement of OPN is particularly significant in advanced EAE. Anti-VLA-4 treatment not only inhibits migration of myelin-reactive T cells, but also downregulates OPN and inhibits loss of oligodendrocytes.
... Studies in animal models of MS (i.e., experimental autoimmune encephalomyelitis, EAE), evidenced that osteopontin administration induces disease reactivation [21] and osteopontindeficient mice showed a milder disease course with decreased inflammatory infiltration, reduced expression of tumor necrosis factor and interferon gamma, and increased production of the anti-inflammatory IL-10 [22,23]. In addition, in line with a possible causal role in acute relapses, neutralizing osteopontin activity with specific antibodies promoted disease remission and improved the clinical course of EAE [24]. Higher osteopontin levels have been found in active MS lesions and in the CSF of patients with MS and other inflammatory neurological conditions [25,26]. ...
... In the proximity of MS relapses, osteopontin expression in CSF may be increased along with other proinflammatory mediators and correlate with decreased concentrations of anti-inflammatory molecules. Modulation of osteopontin activity may represent a future target for personalized MS therapies [24]; however, factors involved in the regulation of osteopontin expression in the acute and chronic phases of the disease and during treatment with DMTs require further investigation. Informed Consent Statement: Written informed consent was obtained from all participants prior to study participation. ...
Background:
Osteopontin, an extracellular matrix protein involved in bone remodeling, tissue repair and inflammation, has previously been associated with increased inflammation and neurodegeneration in multiple sclerosis (MS), promoting a worse disease course. Osteopontin is also likely involved in acute MS relapses.
Methods:
In 47 patients with relapsing-remitting MS, we explored the correlation between the time elapsed between the last clinical relapse and lumbar puncture, and the cerebrospinal fluid (CSF) levels of osteopontin and a group of inflammatory cytokines and adipokines such as resistin, plasminogen activator inhibitor-1, osteoprotegerin, interleukin (IL)-1β, IL-2, IL-6 and IL-1 receptor antagonist (IL-1ra). We also analyzed the correlations between CSF levels of osteopontin and the other CSF molecules considered.
Results:
Osteopontin CSF concentrations were higher in patients with a shorter time interval between the last clinical relapse and CSF withdrawal. In addition, CSF levels of osteopontin were positively correlated with the proinflammatory cytokines IL-2 and IL-6 and negatively correlated with the anti-inflammatory molecule IL-1ra.
Conclusions:
Our results further suggest the role of osteopontin in acute MS relapses showing that, in proximity to relapses, osteopontin expression in CSF may be increased along with other proinflammatory mediators and correlated with decreased concentrations of anti-inflammatory molecules.
... Additionally, the presence of osteopontin-autoantibodies in a subgroup of MS patients was correlated with a reduced number of relapses (Clemente et al., 2017 . In this study, we have used Ly-6C to separate microglia from monocyte-derived macrophages in EAE (Vainchtein et al., 2014). ...
Multiple sclerosis (MS) is the most common inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. Chronic‐relapsing experimental autoimmune encephalomyelitis (crEAE) in Biozzi ABH mice is an experimental model of MS. This crEAE model is characterized by an acute phase with severe neurological disability, followed by remission of disease, relapse of neurological disease and remission that eventually results in a chronic progressive phase that mimics the secondary progressive phase (SPEAE) of MS. In both MS and SPEAE, the role of microglia is poorly defined. We used a crEAE model to characterize microglia in the different phases of crEAE phases using morphometric and RNA sequencing analyses. At the initial, acute inflammation phase, microglia acquired a pro‐inflammatory phenotype. At the remission phase, expression of standard immune activation genes was decreased while expression of genes associated with lipid metabolism and tissue remodeling were increased. Chronic phase microglia partially regain inflammatory gene sets and increase expression of genes associated with proliferation. Together, the data presented here indicate that microglia obtain different features at different stages of crEAE and a particularly mixed phenotype in the chronic stage. Understanding the properties of microglia that are present at the chronic phase of EAE will help to understand the role of microglia in secondary progressive MS, to better aid the development of therapies for this phase of the disease. MAIN POINTS: Microglia switch from a pro‐inflammatory phenotype in acute EAE to a tissue remodeling phenotype in remission. Chronic EAE microglia resemble remission microglia, but show increased proliferation and regain some features of acute phase microglia.
... It was found to be expressed in many cells and organs, including leukocytes, bone cells, breast epithelial cells, the blood and lungs [13,14]. OPN has essential roles in monocyte activation, cytokine release, cell migration, and differentiation in the inflammation process [15]. OPN levels are increased in patients with systemic sepsis [16]. ...
Purpose
The aim of this study is to investigate insulin-like growth factor binding protein 5 (IGFBP5) expression in coronavirus disease 2019 (COVID-19) patients and its relationships with COVID-19 laboratory findings and plasma osteopontin (OPN) levels.
Materials and methods
We enrolled 60 patients with COVID-19 and 30 healthy individuals in this study. mRNA expression of IGFBP5 was measured by RT-PCR. Plasma OPN levels were measured via the ELISA method.
Results
Plasma OPN levels were higher and IGFBP5 expression levels were lower in COVID-19 patients than in the healthy individuals (p = 0.0057 and p = 0.0142, respectively). Critically ill patients had higher OPN and lower IGFBP5 than non-critically ill patients. Patients with affected lungs demonstrated increased OPN and decreased IGFBP5 (p = 0.00032 and p = 0.044, respectively). Receiver operating characteristic (ROC) analysis indicated that IGFBP5 expression and OPN levels can be used discriminate non-critically from critically ill patients (p = 0.049; p = 0.0016, respectively).
Conclusion
This study demonstrated that patients with a poor prognosis had increased OPN and decreased IGFBP5. High values of OPN and low values of IGFBP5 may be considered as signs of disease severity. Tissue-specific IGFBP5 expression may contribute to understanding the role of IGFBP5 in the lungs in COVID-19 cases.
... In vivo and in vitro studies by Hur et al. suggested that OPN promotes the survival of activated immune cells, although it cannot be excluded that this could be an indirect effect mediated by the cytokines attracted by OPN (and not by OPN itself). Moreover, the administration of anti-OPN antibodies reduced clinical severity in EAE models, and vaccination with the OPN-C fragment reduced disease severity and the secretion of pro-inflammatory cytokines by T-cells, indicating that anti-OPN autoantibodies could promote a less aggressive disease course [25]. Secondary progressive MS (SPMS) patients express higher plasma levels of OPN compared to healthy and RRMS patients. ...
... Finally, serum anti-OPN autoantibodies have been detected in MS patients' sera, and their concentration is inversely correlated with the expended disability status scale (EDSS). So, OPN auto-antibodies seem to have an effect on the disease course, and targeted drugs could be proposed for therapy, especially for patients presenting low levels of anti-OPN autoantibodies [25]. ...
Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system which is characterized by demyelinating lesions and axonal damage. MS is a complex disease characterized by important pathophysiological heterogeneity affecting the clinical appearance, progression and therapeutic response for each patient. Therefore, there is a strong unmet need to define specific biomarkers that will reflect the different features of the disease. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the study of MS, as it resembles the pathological features of human MS in many aspects and has allowed for the elucidation of pathogenesis pathways and the validation of certain targets for MS therapies. In this review, we discuss clinically relevant MS molecular biomarkers, divided into five groups based on the key pathological hallmarks of MS: inflammation, blood–brain barrier disruption, myelin and axonal damage, gliosis and, ultimately, repair mechanisms. To address the feasibility of translation between the animal model and human disease, we present an overview of several molecular biomarkers of each category and compare their respective deregulation patterns. We conclude that, like any disease animal model, EAE models can sometimes fail to mimic the entire spectrum of human disease, but they can nonetheless recapitulate the disease’s primary hallmarks. We show that the EAE model is a valuable tool for understanding MS physiopathological mechanisms and for identifying biomarkers fundamental for drug development.
... The molecular weight of OPN varies from 44 to 75 kd, depending on the living organ species and cell types (21). The structure, regulation, physiological, and pathological effects of OPN have been well summarized in the recently published reviews, especially for age-related nonalcoholic fatty liver disease, chronic liver disease, cardiac fibrosis, pulmonary fibrosis, and multiple sclerosis (7,(22)(23)(24)(25). ...
Osteopontin (OPN) is a multifunctional phosphorylated protein. It is widely involved in solid tumor progression, such as intensification of macrophage recruitment, inhibition of T-cell activity, aggravation of tumor interstitial fibrosis, promotion of tumor metastasis, chemotherapy resistance, and angiogenesis. Most of these pathologies are affected by tumor-associated macrophages (TAMs), an important component of the tumor microenvironment (TME). TAMs have been extensively characterized, including their subsets, phenotypes, activation status, and functions, and are considered a promising therapeutic target for cancer treatment. This review focuses on the interaction between OPN and TAMs in mediating tumor progression. We discuss the strategies for targeting OPN and TAMs to treat cancer and factors that may affect the therapeutic outcomes of blocking OPN or depleting TAMs. We also discuss the role of cancer cell- vs. TAM-derived OPN in tumorigenesis, the mechanisms of how OPN affects TAM recruitment and polarization, and why OPN could mediate anti-tumor and pro-tumor effects, as well as previously reported discrepancies.
... 57 These published data sets also provide the opportunity to look at intercellular crosstalk in the human brain. One potentially interesting finding from our analysis (Fig. 3) relates to osteopontin (OPN or SPP1), a proinflammatory cytokine secreted by activated microglia in acute demyelinating lesions in MS. 58 Intriguingly, our analysis revealed that the strength of interactions between microglia-derived OPN and OPC/OL-derived integrin families (ITGA and ITGB) and CD44 differ between MS cases and controls. The effect of OPN on CD44 might specifically involve cell survival (e.g., enhanced survival of myelin reactive T cells). ...
To understand how various brain cell types communicate with each other to orchestrate functional processes, it is crucial to comprehend the signals used to relay such information. Therefore, an important challenge to studying complex brain diseases is to interrogate relevant interactions between cell types. The microglia–oligodendroglia interaction is an important example that has fundamental roles in physiological state and brain pathologies. Here, we review the latest findings on microglia–oligodendroglia interplay in physiological and pathological conditions. Furthermore, we provide an in silico ligand–receptor interaction analysis to explore potential druggable targets in multiple sclerosis (MS) and major depressive disorder (MDD).
