Content uploaded by Jula Huppert
Author content
All content in this area was uploaded by Jula Huppert on Mar 12, 2014
Content may be subject to copyright.
A preview of the PDF is not available
Cellular mechanisms of IL-17-induced blood-brain barrier disruption
The FASEB Journal
Abstract and Figures
Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd.3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase- or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption.
Figures - uploaded by Jula Huppert
Author content
All figure content in this area was uploaded by Jula Huppert
Content may be subject to copyright.
... IL-17 upregulates the expression of CCL20 on choroidal epithelial cells and promotes the entry of Th17 cells into the subarachnoid space [50]. IL-17 can disrupt the integrity of the blood-brain barrier (BBB) through downregulation of occludin and activation of the endothelial contractile machinery [51]. Transmigrated Th17 cells, by secreting IL-17, further stimulate the release of the chemokine CCL2 from endothelial cells, resulting in BBB disruption [52]. ...
Glioblastoma (GBM) is the most common malignant brain tumor, which, despite significant progress made in the last years in the field of neuro-oncology, remains an incurable disease. GBM has a poor prognosis with a median survival of 12–15 months, and its aggressive clinical course is related to rapid growth, extensive infiltration of adjacent tissues, resistance to chemotherapy, radiotherapy and immunotherapy, and frequent relapse. Currently, several molecular biomarkers are used in clinical practice to predict patient prognosis and response to treatment. However, due to the overall unsatisfactory efficacy of standard multimodal treatment and the remaining poor prognosis, there is an urgent need for new biomarkers and therapeutic strategies for GBM. Recent evidence suggests that GBM tumorigenesis is associated with crosstalk between cancer, immune and stromal cells mediated by various cytokines. One of the key factors involved in this process appears to be interleukin-17 (IL-17), a pro-inflammatory cytokine that is significantly upregulated in the serum and tissue of GBM patients. IL-17 plays a key role in tumorigenesis, angiogenesis, and recurrence of GBM by activating pro-oncogenic signaling pathways and promoting cell survival, proliferation, and invasion. IL-17 facilitates the immunomodulation of the tumor microenvironment by promoting immune cells infiltration and cytokine secretion. In this article we review the latest scientific reports to provide an update on the role of IL-17 role in tumorigenesis, tumor microenvironment, diagnosis, prognosis, and treatment of GBM.
... During acute inflammation, there is without peripheral immune response involved but over the time chronic inflammation it leads to cause the degradation of blood-brain barrier tissue and provide the access of Neuro invasion and resulting CNS is not well protected by the BBB and microglial cell will lead to produce reactive oxygen species and it will then lead to release of cytokines like IL-1, IL-4, IL-6, IL-18, TNF-α, IL-1β. It produced these pro-inflammatory cytokines from activated microglial cells, astrocyte endothelial cells at the site of infection or injury in the brain (Huppert et al. 2010;Chen et al. 2014;Chen et al. 2012;Kim et al. 2016a, b). These cytokines act as neuromodulators. ...
... During acute inflammation, there is without peripheral immune response involved but over the time chronic inflammation it leads to cause the degradation of blood-brain barrier tissue and provide the access of Neuro invasion and resulting CNS is not well protected by the BBB and microglial cell will lead to produce reactive oxygen species and it will then lead to release of cytokines like IL-1, IL-4, IL-6, IL-18, TNF-α, IL-1β. It produced these pro-inflammatory cytokines from activated microglial cells, astrocyte endothelial cells at the site of infection or injury in the brain (Huppert et al. 2010;Chen et al. 2014;Chen et al. 2012;Kim et al. 2016a, b). These cytokines act as neuromodulators. ...
Japanese Encephalitis remains a significant global health concern, contributing to millions of deaths annually worldwide. Microglial cells, as key innate immune cells within the central nervous system (CNS), exhibit intricate cellular structures and possess molecular phenotypic plasticity, playing pivotal roles in immune responses during CNS viral infections. Particularly under viral inflammatory conditions, microglial cells orchestrate innate and adaptive immune responses to mitigate viral invasion and dampen inflammatory reactions. This review article comprehensively summarizes the pathophysiology of viral invasion into the CNS and the cellular interactions involved, elucidating the roles of various immune mediators, including pro-inflammatory cytokines, in neuroinflammation. Leveraging this knowledge, strategies for modulating inflam-matory responses and attenuating hyperactivation of glial cells to mitigate viral replication within the brain are discussed. Furthermore, current chemotherapeutic and antiviral drugs are examined, elucidating their mechanisms of action against viral replication. This review aims to provide insights into therapeutic interventions for Japanese Encephalitis and related viral infections, ultimately contributing to improved outcomes for affected individuals.
... IL-17 production affects BBB function and promotes lymphocyte and monocyte migration [186]. IL-17 induces ROS production in ECs via the NOX and xanthine-oxidase enzymes resulting in BBB functional impairment [197]. Infiltrating macrophages continue oxidative damage in active demyelinating lesions, destabilizing the BBB further [198]. ...
The blood-brain barrier (BBB) regulates the exchange of metabolites and cells between the blood and brain, and maintains central nervous system homeostasis. Various factors affect BBB barrier functions, including reactive oxygen species (ROS). ROS can act as stressors, damaging biological molecules, but they also serve as secondary messengers in intracellular signaling cascades during redox signaling. The impact of ROS on the BBB has been observed in multiple sclerosis, stroke, trauma, and other neurological disorders, making blocking ROS generation a promising therapeutic strategy for BBB dysfunction. However, it is important to consider ROS generation during normal BBB functioning for signaling purposes. This review summarizes data on proteins expressed by BBB cells that can be targets of redox signaling or oxidative stress. It also provides examples of signaling molecules whose impact may cause ROS generation in the BBB, as well as discusses the most common diseases associated with BBB dysfunction and excessive ROS generation, open questions that arise in the study of this problem, and possible ways to overcome them.
... Among the six isoforms of IL-17, no other subtypes have been found to be expressed or related signaling pathways in CNS except IL-17A [45]. In vivo and in vitro experiments show that Th17 cells can infiltrate into the brain [46,47], while IL-17A can destroy the blood-brain barrier (BBB) [48]. Intrathecal injection of Aβ-42 peptides was used to establish an AD rat model, and it was found that after Th17 cells entered the central nervous system, the permeability of BBB increased, and the levels of IL-17A and RORγt in the hippocampus, cerebrospinal fluid, and serum increased [49]. ...
Background
Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats.
Methods
Male wild-type Wistar rats aged 11–12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1β, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence.
Results
The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1β (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased.
Conclusion
PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.
... Т-киллеры, несущие гликопротеины кластера дифференцировки 8 (cluster of differentiation 8, CD8 + ), будучи сенсибилизированными к антигенам миелина, оказывают прямое цитотоксическое действие, в то время как CD4 + Т-хелперы, в частности популяции Т-хелперов 1 и 17, способствуют дальнейшему прогрессированию воспаления за счет синтеза провоспалительных цитокинов. Так, Т-хелперы 1 продуцируют интерферон-гамма [49], в то время как Т-хелперы 17 синтезируют ИЛ-17, который не только способствует активации клеток микроглии [50,51], но и вносит вклад в дестабилизацию ГЭБ [52], приводя к усилению притока воспалительных клеток в ЦНС [53]. В-клетки также участвуют в патогенезе РС, как за счет образования аутоантител [54,55] и цитокинов [48] (преимущественно при первично-прогрессирующем типе), так и за счет презентации антигенов Т-клеткам (при рецидивирующем течении заболевания) [48]. ...
Autoimmune diseases are characterized by dysregulation of immune responses and damage to healthy body tissues. Their complete cure remains elusive, and existing therapies are often accompanied by side effects. Recent studies have shown a signifi cant role of disturbances in the composition of the microbiome in the development of autoimmune reactions. Moreover, modulation of the microbiome through various therapeutic interventions represents a promising direction in the framework of complex therapy of the underlying disease. Extracellular vesicles, in particular exosomes, transport biologically active substances between cells, and a number of studies have shown their therapeutic effect in autoimmune diseases. However, the role of extracellular vesicles in modulating the microbiome remains poorly understood, and further research is needed to better understand their impact on the pathogenesis of autoimmune diseases and associated microbiome changes, as well as to develop new treatment strategies. The presented literature review, based on a study of English-language sources, examines the importance of the microbiota of different loci of the human body (intestines, skin, oral cavity) in the development of autoimmune diseases such as multiple sclerosis, psoriasis and Sjögren’s disease. The role of extracellular vesicles in modulating the microbiome during autoimmune diseases therapy is discussed.
Intracerebral hemorrhage (ICH) is a common cerebrovascular disease that can lead to severe neurological dysfunction in surviving patients, resulting in a heavy burden on patients and their families. When ICH occurs, the blood‒brain barrier is disrupted, thereby promoting immune cell migration into damaged brain tissue. As important immunosuppressive T cells, regulatory T (Treg) cells are involved in the maintenance of immune homeostasis and the suppression of immune responses after ICH. Treg cells mitigate brain tissue damage after ICH in a variety of ways, such as inhibiting the neuroinflammatory response, protecting against blood‒brain barrier damage, reducing oxidative stress damage and promoting nerve repair. In this review, we discuss the changes in Treg cells in ICH clinical patients and experimental animals, the mechanisms by which Treg cells regulate ICH and treatments targeting Treg cells in ICH, aiming to support new therapeutic strategies for clinical treatment.
Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt–Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood–brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions.
The susceptibility to autoimmune diseases is conditioned by the association of modest genetic alterations which altogether weaken self-tolerance. The mechanism whereby these genetic interactions modulate T-cell pathogenicity remains largely uncovered. Here, we investigated the epistatic interaction of two interacting proteins involved in T Cell Receptor signaling and which were previously associated with the development of Multiple Sclerosis. To this aim, we used mice expressing an hypomorphic variant of Vav1 (Vav1R63W), combined with a T cell-conditional deletion of Themis. We show that the combined mutations in Vav1 and Themis induce a strong attenuation of the severity of Experimental Autoimmune Encephalomyelitis (EAE), contrasting with the moderate effect of the single mutation in each of those two proteins. This genotype-dependent gradual decrease of EAE severity correlates with decreased quantity of phosphorylated Vav1 in CD4 T cells, establishing that Themis promotes the development of encephalitogenic Tconv response by enhancing Vav1 activity. We also show that the cooperative effect of Themis and Vav1 on EAE severity is independent of regulatory T cells and unrelated to the impact of Themis on thymic selection. Rather, it results from decreased production of pro-inflammatory cytokines (IFN-γ, IL-17, TNF and GM-CSF) and reduced T cell infiltration in the CNS. Together, our results provide a rationale to study combination of related genes, in addition to single gene association, to better understand the genetic bases of human diseases.
The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell-specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell-driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F-deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of autoreactive T cells during disease. To eliminate potential compensatory effects of either cytokine, we treated IL-17F-deficient mice with antagonistic monoclonal antibodies specific for IL-17A and found again only a minimal beneficial impact on disease development. We conclude therefore that both IL-17A and IL-17F, while prominently expressed by an encephalitogenic T cell population, may only marginally contribute to the development of autoimmune CNS disease.
We have investigated the expression of vascular adhesion molecules during the first stage of chronic inflammation in experimental autoimmune encephalomyelitis in the SJL/J mouse. Immunocytochemical analysis of frozen sections of inflamed versus noninflamed brains and spinal cords showed that the vascular endothelium in brains and spinal cords from diseased animals expressed high levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) but no detectable mucosal addressin or peripheral lymph node addressin. In frozen section assays, anti-alpha 4 integrin and anti-VCAM-1 monoclonal antibodies inhibited binding of mouse peripheral lymphocytes to inflamed brains at both 4 C and 20 C. Antilymphocyte function-associated antigen-1 and anti-ICAM-1 monoclonal antibodies inhibited binding of mouse peripheral lymphocytes to inflamed brains at 20 C. These results are consistent with an important role for the vascular adhesion molecules VCAM-1 and ICAM-1 and for their lymphocytes receptors in lymphocyte recruitment to the central nervous system.
The transcription level of the rat p53 gene increases at 5-12 h in the regenerating liver after partial hepatectomy. It was previously reported that an activator protein 1 (AP1)-like element (-264 - 284) mediated the induced transcription of the rat p53 gene during liver regeneration. In this study, we characterize the protein binding to the AP1-like element by various methods. Oligonucleotide competition assays showed that the binding protein did not require AP1 consensus sequence. Therefore, the binding protein is not an AP1 family protein. Zn²⁺ was required for maximum DNA-binding activity of the protein, suggesting that the binding protein contains zinc fingers. The binding protein was highly resistant to denaturant. Even 1.8 M urea did not eliminate the protein-DNA complexes. In addition, the binding protein was stable up to 55°C. The protein-DNA complexes were abolished in the presence of 0.6 M NaCl and higher. Protease clipping assay showed that the protein had a protease-resistant core DNA binding domain. These results provided new insights into the structure of the protein that binds to the AP1-like element of the p53 promoter during liver regeneration.
Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell–mediated or T-cell plus antibody–mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease—as reflected in autopsy cases—the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease. Ann Neurol 2000;47:707–717
Myelin-directed autoimmunity is considered to Ploy a key role in the pathogenesis of multiple sclerosis (MS). increased Production of both pro- and anti-inflammatory cytokines is a common finding in MS. Interleukin-17 (IL-17) is a recently described cytokine produced in humans almost exclusively by activated memory T cells, which con induce the production of proinflammatory cytokines and chemokines from parenchymal cells and macrophages. In situ hybridisation with synthetic oligonucleotide probes was adopted to detect and enumerate IL-17 mRNA expressing mononuclear cells (MNC) in blood and cerebrospinal fluid (CSF) from patients with MS and control individuals. Numbers of IL-17 mRNA expressing blood MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM) compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood MNC were detected in MS patients examined during clinical exacerbation compared to remission. Patients with MS had higher numbers of IL-17 mRNA expressing MNC in CSF compared to blood. This increase in numbers of IL-17 mRNA expressing MNC in CSF was not observed in patients with AM. Our results thus demonstrate increased numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood, and with the highest numbers in blood during clinical exacerbations.
Endothelial cells are known to produce reactive oxygen species by several mechanisms. Functional consequences of increased production of reactive oxygen species were investigated in vitro after stimulation with several proinflammatory cytokines. Time dependent increases in DCF-fluorescence as a measure of reactive oxygen load were quantified in single cells after incubation with TNF-, IL-1 and IFN-. The increased DCF-fluorescence was inhibited by cell permeant antioxidative substances Tiron and Tempol. NMMA, an inhibitor of nitric oxide synthase reduced endothelial DCF-fluorescence only marginally, indicating a minor participation of nitric oxide production in this detection system. Cytokine induced endothelial DCF-fluorescence increased in the presence of NADH, whereas coincubation with NADPH or xanthine was without effect. Flavoenzyme inhibitor diphenyliodonium abolished stimulated DCF-fluorescence. Cytokine induced release of MCP-1 and IL-6 by endothelial cells was completely inhibited in the presence of Tiron and Tempol, whereas NMMA was less effective. Collectively these data indicate that cytokine stimulated endothelial cells increase their reactive oxygen species production probably via NADH oxidase and this production may critically be involved in the secretion of MCP-1 and IL-6.
The primary function of Th17 cells appears to be the clearance of extracellular pathogens during infections. However, Th17 cells also promote inflammation and have been implicated in the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions. Transforming growth factor beta (TGFbeta) is a critical differentiation factor for the generation of regulatory T (T-reg) cells, whereas the combination of interleukin 6 (IL6) and TGFbeta induces the differentiation of pathogenic Th17 cells. Therefore, it is proposed that at the steady state (in the absence of any inflammatory stimuli), TGFbeta, which is produced by various cells types including naturally occurring T-reg (nT-reg) cells, encourages the generation of induced T-reg (iT-reg) cells, which together with nT-reg cells keep autoreactive T cells under check. IL6, an acute phase protein produced by the activated immune system, inhibits the function of T-reg cells and instead promotes the differentiation of Th17 cells. Thus, IL6 plays a pivotal role in dictating the balance between the generation of T-reg and Th17 cells. This reciprocal relationship between T-reg and Th17 cells is further supported by the results obtained in IL6(-/-) mice, which show a severe defect in the generation of Th17 cells and increased numbers of T-reg cells in the peripheral repertoire.
Increased mortality after stroke is associated with brain edema formation and high plasma levels of the acute phase reactant C-reactive protein (CRP). The aim of this study was to examine whether CRP directly affects blood-brain barrier stability and to analyze the underlying signaling pathways.
We used a cell coculture model of the blood-brain barrier and the guinea pig isolated whole brain preparation.
We could show that CRP at clinically relevant concentrations (10 to 20 microg/mL) causes a disruption of the blood-brain barrier in both approaches. The results of our study further demonstrate CRP-induced activation of surface Fcgamma receptors CD16/32 followed by p38-mitogen-activated protein kinase-dependent reactive oxygen species formation by the NAD(P)H-oxidase. The resulting oxidative stress increased myosin light chain kinase activity leading to an activation of the contractile machinery. Blocking myosin light chain phosphorylation prevented the CRP-induced blood-brain barrier breakdown and the disruption of tight junctions.
Our data identify a previously unrecognized mechanism linking CRP and brain edema formation and present a signaling pathway that offers new sites of therapeutic intervention.
Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood-brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.