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1.
J Neuroinflammation ; 21(1): 8, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178143

RESUMO

Progressive brain diseases create a huge social and economic burden on modern societies as a major cause of disability and death. Incidence of brain diseases has a significantly increasing trend and merits new therapeutic strategies. At the base of many progressive brain malfunctions is a process of unresolved, chronic inflammation. Macrophage migration inhibitory factor, MIF, is an inflammatory mediator that recently gained interest of neuro-researchers due to its varied effects on the CNS such as participation of nervous system development, neuroendocrine functions, and modulation of neuroinflammation. MIF appears to be a candidate as a new biomarker and target of novel therapeutics against numerous neurologic diseases ranging from cancer, autoimmune diseases, vascular diseases, neurodegenerative pathology to psychiatric disorders. In this review, we will focus on MIF's crucial role in neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) and glioblastoma (GBM).


Assuntos
Encefalopatias , Fatores Inibidores da Migração de Macrófagos , Esclerose Múltipla , Doenças do Sistema Nervoso , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , Inflamação , Calgranulina A , Calgranulina B , Oxirredutases Intramoleculares
2.
Metab Brain Dis ; 38(2): 589-599, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36454506

RESUMO

BACKGROUND: IL-10 knockout (KO) mice can be protected against experimental autoimmune encephalomyelitis (EAE) with low-dose estrogen (E2) treatment similar to wild type (WT) mice, indicating that IL-10 is not required for E2-induced EAE protection. Our previous study demonstrated that E2 treatment induced an increase in programmed death ligands 1 (PD-L1) and 2 (PD-L2) on monocytes and macrophages in the periphery and within the CNS. In this study, we selectively inhibited the function of PD-L1 and PD-L2 to evaluate their critical role in maintaining E2-induced protection against EAE in IL-10-KO mice. METHODS: This study used female IL-10 KO mice pre-treated with either E2 or sham pellets seven days prior to induction of EAE and subsequently treated with Vehicle or antibodies to PD-L1, PD-L2 or respective isotype controls. Mice were scored daily for EAE severity over 21 days post-EAE induction. Cells from the spleen and brain were evaluated by flow cytometry. RESULTS: Differences in EAE severity were assessed in E2 and sham pre-treated IL-10-KO mice treated with α-PD-L1 or α-PD-L2 antibodies over the course of disease compared to treatment with Vehicle or isotype control antibodies. The results revealed real-time development of severe EAE in E2-pre-treated IL-10-KO mice treated with α-PD-L1 but not α-PD-L2 antibodies, mediated in part by increased percentages of activated CD74+CD11b+ myeloid cells in spleen and brain as well as splenic B-cells, T-cells and CD73+ cells. CONCLUSION: These results demonstrate unequivocally that PD-L1 but not PD-L2 was required to retain the inhibitory effects of E2 on clinical EAE scores in female IL-10-KO mice and further implicate the emergence of the MIF/CD74 axis as a contributing pathogenic mechanism.


Assuntos
Encefalomielite Autoimune Experimental , Animais , Feminino , Camundongos , Antígeno B7-H1 , Encéfalo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Estrogênios/farmacologia , Interleucina-10 , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Metab Brain Dis ; 38(7): 2383-2391, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37341855

RESUMO

Multiple sclerosis (MS) is the most common causes of non-traumatic disability in young adults worldwide. MS pathophysiologies include the formation of inflammatory lesions, axonal damage and demyelination, and blood brain barrier (BBB) disruption. Coagulation proteins, including factor (F)XII, can serve as important mediators of the adaptive immune response during neuroinflammation. Indeed, plasma FXII levels are increased during relapse in relapsing-remitting MS patients, and previous studies showed that reducing FXII levels was protective in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our objective was to determine if pharmacological targeting of FXI, a major substrate of activated FXII (FXIIa), improves neurological function and attenuates CNS damage in the setting of EAE. EAE was induced in male mice using murine myelin oligodendrocyte glycoprotein peptides combined with heat-inactivated Mycobacterium tuberculosis and pertussis toxin. Upon onset of symptoms, mice were treated every other day intravenously with anti-FXI antibody, 14E11, or saline. Disease scores were recorded daily until euthanasia for ex vivo analyses of inflammation. Compared to the vehicle control, 14E11 treatment reduced the clinical severity of EAE and total mononuclear cells, including CD11b+CD45high macrophage/microglia and CD4+ T cell numbers in brain. Following pharmacological targeting of FXI, BBB disruption was reduced, as measured by decreased axonal damage and fibrin(ogen) accumulation in the spinal cord. These data demonstrate that pharmacological inhibition of FXI reduces disease severity, immune cell migration, axonal damage, and BBB disruption in mice with EAE. Thus, therapeutic agents targeting FXI and FXII may provide a useful approach for treating autoimmune and neurologic disorders.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Masculino , Camundongos , Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Fator XI/antagonistas & inibidores , Fator XI/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Medula Espinal/metabolismo
4.
Cell Immunol ; 378: 104561, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35738135

RESUMO

Our previous studies demonstrated increased serum levels of macrophage migration inhibitory factor (MIF-1) and its homologue, MIF-2, in males during MS progression; and that genetically high-MIF-expressing male subjects with relapsing multiple sclerosis (MS) had a significantly greater risk of conversion to progressive MS than lower-MIF-expressing males and females. However, female MS subjects with severe disease expressed higher levels of CD74, the common MIF-1/MIF-2 receptor, on blood cells. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), both male and female mice lacking MIF-1 and/or MIF-2 were clinically improved during development of moderately severe disease, thus implicating both homologs as co-pathogenic contributors. The current study using MIF-deficient mice with severe acute EAE revealed a highly significant reduction of EAE scores in MIF-1-deficient females, in contrast to only minor and delayed reduction of clinical signs in MIF-1-deficient males. However, clinical EAE scores and factor expression were strongly suppressed in males and further reduced in females after treatment of WT and MIF-1-, MIF-2- and MIF-1/2-DUAL-deficient female and male mice with a MHCII DRα1-MOG-35-55 molecular construct that competitively inhibits MIF-1 & MIF-2 signaling through CD74 as well as T cell activation. These results suggest sex-dependent differences in which the absence of the MIF-1 and/or MIF-2 genotypes may permit stronger compensatory CD74-dependent EAE-inducing responses in males than in females. However, EAE severity in both sexes could still be reduced nearly to background (a "near cure") with DRα1-MOG-35-55 blockade of compensatory MIF and CD74-dependent factors known to attract peripheral inflammatory cells into the spinal cord tissue.


Assuntos
Encefalomielite Autoimune Experimental , Hormônio Inibidor da Liberação de MSH , Fatores Inibidores da Migração de Macrófagos , Esclerose Múltipla , Animais , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Hormônio Inibidor da Liberação de MSH/metabolismo , Hormônio Inibidor da Liberação de MSH/uso terapêutico , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medula Espinal
5.
J Neuroinflammation ; 18(1): 298, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34949203

RESUMO

The brain is unique and the most complex organ of the body, containing neurons and several types of glial cells of different origins and properties that protect and ensure normal brain structure and function. Neurological disorders are the result of a failure of the nervous system multifaceted cellular networks. Although great progress has been made in the understanding of glia involvement in neuropathology, therapeutic outcomes are still not satisfactory. Here, we discuss recent perspectives on the role of microglia and astrocytes in neurological disorders, including the two most common neurodegenerative conditions, Alzheimer disease and progranulin-related frontotemporal lobar dementia, as well as astrocytoma brain tumors. We emphasize key factors of microglia and astrocytic biology such as the highly heterogeneic glial nature strongly dependent on the environment, genetic factors that predispose to certain pathologies and glia senescence that inevitably changes the CNS landscape. Our understanding of diverse glial contributions to neurological diseases can lead advances in glial biology and their functional recovery after CNS malfunction.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Microglia/patologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Animais , Humanos
6.
Cell Immunol ; 370: 104439, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34607646

RESUMO

Macrophage migration inhibitory factor (MIF-1) and its homologue d-dopachrome tautomerase (MIF-2) share the common CD74 receptor and function innately to enhance severity of multiple sclerosis (MS) as well as the experimental autoimmune encephalomyelitis (EAE) model for MS. We previously demonstrated that genetically high-MIF-expressing male subjects with relapsing MS had a significantly greater risk of conversion to progressive MS (PMS) than lower-MIF-expressing males. To expand on this observation, we utilized MIF-1, MIF-2, and MIF-1/2-DUAL-deficient male mice to discern if there would be a greater contribution of these inflammatory factors in EAE mice with severe vs. moderate clinical disease signs. As shown previously, mice deficient in either MIF-1 or MIF-2 each had a ∼25% reduction of moderate EAE compared to WT mice, with significant differences in disease onset and trajectory. However, EAE induction in mice deficient in both MIF-1 and MIF-2 genes did not result in a further reduction in EAE severity. This result suggests that the two MIF homologues were likely affecting the same pathogenic pathways such that each could partially compensate for the other but not in an additive or synergistic manner. However, MIF-1-KO, MIF-2-KO, and MIF-1/2-DUAL-KO mice with severe EAE did not exhibit a significant reduction in cumulative EAE scores compared with WT mice, but the MIF-1-KO and, to a lesser extent, MIF-1/2-DUAL-KO mice did show a significant reduction in daily EAE scores over the last 3 days of observation, and MIF-2-KO mice showed a more modest but still consistent reduction over the same span. Furthermore, deletion of MIF-1 resulted in a massive reduction in the expression of EAE- and Complete Freund's Adjuvant-associated inflammatory factors, suggesting delayed involvement of the MIF/CD74 axis in promoting disease expression. To further explore modulation of MIF-1 and MIF-2 effects on EAE, we treated WT mice with moderate EAE using DRα1-mMOG-35-55, an inhibitor of CD74 that blocks both MIF-1 and MIF-2 action. This treatment reduced ongoing moderate EAE severity in excess of 25%, suggesting efficient blockade of the MIF/CD74 axis in disease-enhancing pathways. Moreover, DRα1-mMOG-35-55 treatment of mice with severe EAE strongly reversed EAE- and CFA-associated expression of inflammatory cytokines and chemokines including Tnf, Ccr7, Ccr6, Ccl8, Cxcr3, and Ccl19 in MIF-deficient mouse genotypes, and also exceeded innate MIF-1 and MIF-2 EAE enhancing effects, especially in MIF-1-KO mice. These results illustrate the therapeutic potential of targeting the disease-enhancing MIF/CD74 pathway in male mice with moderate and severe EAE, with implications for treatment of high-MIF-expressing RRMS human males at risk of conversion to progressive MS as well as those that have already transitioned to PMS.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Fármacos Neuroprotetores/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Cell Immunol ; 359: 104242, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33190849

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is commonly used as an animal model for evaluating clinical, histological and immunological processes potentially relevant to the human disease multiple sclerosis (MS), for which the mode of disease induction remains largely unknown. An important caveat for interpreting EAE processes in mice is the inflammatory effect of immunization with myelin peptides emulsified in Complete Freund's Adjuvant (CFA), often followed by additional injections of pertussis toxin (Ptx) in some strains to induce EAE. The current study evaluated clinical, histological, cellular (spleen), and chemokine-driven processes in spinal cords of male vs. female C57BL/6 mice that were immunized with mouse (m)MOG-35-55/CFA/Ptx to induce EAE; immunized with saline/CFA/Ptx only (CFA, no EAE); or were untreated (Naïve, no EAE). Analysis of response curves utilized a rigorous and sophisticated methodology to parse and characterize the effects of EAE and adjuvant alone vs. the Naive baseline responses. The results demonstrated stronger pro-inflammatory responses of immune cells and their associated cytokines, chemokines, and receptors in male vs. female CFA and EAE mice that appeared to be offset partially by increased percentages of male anti-inflammatory, regulatory and checkpoint T cell, B cell, and monocyte/macrophage subsets. These sex differences in peripheral immune responses may explain the reduced cellular infiltration and differing chemokine profiles in the Central Nervous System (CNS) of male vs. female CFA immunized mice and the reduced CNS infiltration and demyelination observed in male vs. female EAE groups of mice that ultimately resulted in the same clinical EAE disease severity in both sexes. Our findings suggest EAE disease severity is governed not only by the degree of CNS infiltration and demyelination, but also by the balance of pro-inflammatory vs. regulatory cell types and their secreted cytokines and chemokines.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Adjuvante de Freund/farmacologia , Adjuvantes Imunológicos/farmacologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Sistema Nervoso Central/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Imunização/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Fragmentos de Peptídeos/imunologia , Toxina Pertussis/farmacologia , Caracteres Sexuais , Fatores Sexuais , Medula Espinal/imunologia , Linfócitos T/imunologia
8.
Proc Natl Acad Sci U S A ; 114(40): E8421-E8429, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28923927

RESUMO

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a -794CATT5-8 microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.


Assuntos
Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/fisiologia , Esclerose Múltipla/patologia , Índice de Gravidade de Doença , Adulto , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Polimorfismo Genético
9.
J Neuroinflammation ; 16(1): 14, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30683115

RESUMO

Neurovascular, autoimmune, and traumatic injuries of the central nervous system (CNS) all have in common an initial acute inflammatory response mediated by influx across the blood-brain barrier of activated mononuclear cells followed by chronic and often progressive disability. Although some anti-inflammatory therapies can reduce cellular infiltration into the initial lesions, there are essentially no effective treatments for the progressive phase. We here review the successful treatment of animal models for four separate neuroinflammatory and neurodegenerative CNS conditions using a single partial MHC class II construct called DRa1-hMOG-35-55 or its newest iteration, DRa1(L50Q)-hMOG-35-55 (DRhQ) that can be administered without a need for class II tissue type matching due to the conserved DRα1 moiety of the drug. These constructs antagonize the cognate TCR and bind with high affinity to their cell-bound CD74 receptor on macrophages and dendritic cells, thereby competitively inhibiting downstream signaling and pro-inflammatory effects of macrophage migration inhibitory factor (MIF) and its homolog, D-dopachrome tautomerase (D-DT=MIF-2) that bind to identical residues of CD74 leading to progressive disease. These effects suggest the existence of a common pathogenic mechanism involving a chemokine-driven influx of activated monocytes into the CNS tissue that can be reversed by parenteral injection of the DRa1-MOG-35-55 constructs that also induce anti-inflammatory macrophages and microglia within the CNS. Due to their ability to block this common pathway, these novel drugs appear to be prime candidates for therapy of a wide range of neuroinflammatory and neurodegenerative CNS conditions.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/terapia , Anti-Inflamatórios/uso terapêutico , Lesões Encefálicas Traumáticas/terapia , Isquemia Encefálica/terapia , Esclerose Múltipla/terapia , Animais , Antiportadores de Cloreto-Bicarbonato , Humanos , Glicoproteína Mielina-Oligodendrócito/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Transportadores de Sulfato
10.
J Neuroinflammation ; 16(1): 195, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665042

RESUMO

BACKGROUND: IL-10 knockout (KO) mice are protected from experimental autoimmune encephalomyelitis (EAE) with low-dose estrogen (E2) treatment similar to wild-type (WT) mice. Previous studies have demonstrated a decrease in tumor necrosis factor in all E2-treated groups, which led to the protection of the mice. METHODS: This study used IL-10 KO mice and WT mice treated either with E2 or sham pellets 7 days prior to induction of EAE. Mice were observed for 21 days post-immunization. The spleen, inguinal lymph nodes, and brain were evaluated by flow cytometry. Spinal cords were evaluated using a cytokine/chemokine array, RT-PCR, and histology. RESULTS: This study demonstrates that E2 treatment induced three heightened regulatory mechanisms that potentially protect IL-10 KO mice from EAE: (1) an increase in programmed death-ligands 1 and 2 on monocytes and macrophages in the periphery and within the CNS; (2) an increase in CD73 in the inflamed CNS, which can increase the production of the anti-inflammatory molecule adenosine; and (3) a decrease in CD4+CD25+FoxP3+ regulatory T cells in the spleen. Together, these factors comprise an alternative compensatory mechanism that significantly downregulates key pro-inflammatory cytokine, chemokine, and chemokine receptor genes which are enhanced in the spinal cord of IL-10 KO mice. This group of E2-treated mice remained asymptomatic after EAE challenge similar to E2-treated WT mice, despite their having more T and B lymphocytes in the brain, and modestly increased demyelination in the spinal cord. CONCLUSION: These results indicate that previously unrecognized compensatory mechanisms of EAE protection are stimulated by E2 in the absence of IL-10, which can provide disease protection comparable to the IL-10-dependent effects induced by E2 in WT mice.


Assuntos
Implantes de Medicamento/administração & dosagem , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Estrogênios/administração & dosagem , Interleucina-10/deficiência , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Metab Brain Dis ; 34(6): 1705-1712, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31410774

RESUMO

Inflammation involving migration of immune cells across the damaged blood-brain barrier (BBB), activation of resident innate microglia and production of inflammatory humoral mediators such as cytokines and chemokines play a critical role in the pathogenesis of ischemic stroke. Cell-cell signaling involved in the process also includes checkpoint interaction between programmed death receptor (PD1) and programmed death ligands, PDL1 and PDL2. Based on our previous studies showing reduced MCAO infarct volumes in PDL2 deficient mice, we evaluated the ability of anti-PDL2 mAb to treat MCAO in male and female C57BL/6 mice. We found that anti-PDL2 neutralizing antibody treatment of MCAO significantly reduced infarct volumes in male mice but had no protective effects in female mice even at a 5-fold increased dose of anti-PDL2 mAb. The protection in male mice was likely mediated by reduced percentages in the spleen of PDL2+CD19+ B cells, PDL1+CD4+ T cells and CD86+CD11b+ macrophages in concert with reduced expression of PDL1 and TNFα and continued expression of CD206, in the injured ipsilateral brain hemisphere. The lack of a therapeutic benefit of anti-PDL2 on stroke-induced infarct volumes in female mice was reflected by no detectable reduction in expressed PDL2 or PDL1 and an increased frequency of Th1 and Th17 pro-inflammatory T cell subsets in the spleen, an effect not seen in PDL2 mAb treated males. This result potentially limits the utility of anti-PDL2 mAb therapy in stroke to males but underscores the importance of meeting the STAIR requirements for development of new stroke therapies for both sexes.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Acidente Vascular Cerebral/tratamento farmacológico , Subpopulações de Linfócitos T/imunologia , Animais , Modelos Animais de Doenças , Feminino , Infarto da Artéria Cerebral Média/imunologia , Masculino , Camundongos , Fatores Sexuais , Acidente Vascular Cerebral/imunologia , Resultado do Tratamento
12.
Metab Brain Dis ; 34(1): 153-164, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353480

RESUMO

Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system (CNS) with a strong inflammatory component that affects more than 2 million people worldwide (and at least 400,000 in the United States). In MS, macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) enhance the inflammatory event as a result of their interaction with their cognate receptor CD74. Therefore, the search for new agents aimed at blocking this interaction is critical for therapeutic purposes and will be of paramount importance for the treatment of MS. DRα1-MOG-35-55 constructs have been demonstrated to be effective in the treatment of experimental autoimmune encephalomyelitis (EAE) a mouse model for MS. This effect is directly correlated with the binding to its cell surface receptor, CD74, apparently preventing or blocking the binding of two inflammatory factors, MIF and D-DT. Here we report that a single amino acid substitution (L50Q) in the DRα1 domain of the human and mouse DRα1-MOG-35-55 constructs (notated as DRhQ and DRmQ, respectively) possessed increased affinity for CD74, a greater capacity to block MIF binding, the ability to inhibit pERK1/2 signaling and increased therapeutic activity in mice with EAE. These data suggest that binding affinity for CD74 could serve as an in vitro indicator of biological potency of DRhQ and thus support its possible clinical utility as an effective therapy for MS and perhaps other diseases in which there is an inflammatory reaction driven by MIF and D-DT.


Assuntos
Antígenos de Diferenciação de Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Antígenos de Histocompatibilidade Classe II/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Encefalomielite Autoimune Experimental/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Transdução de Sinais/fisiologia , Resultado do Tratamento
13.
Immunology ; 154(2): 169-177, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29313944

RESUMO

Current treatment options for human stroke are limited mainly to the modestly effective infusion of tissue plasminogen activator (tPA), with additional improvement of functional independence and higher rates of angiographic revascularization observed after mechanical thrombectomy. However, new therapeutic strategies that address post-stroke immune-mediated inflammatory responses are urgently needed. Recent studies in experimental stroke have firmly implicated immune mechanisms in the propagation and partial resolution of central nervous system damage after the ischaemic event. A new-found anti-inflammatory role for regulatory B (Breg) cells in autoimmune diseases sparked interest in these cells as potential immunomodulators in stroke. Subsequent studies identified interleukin-10 as a common regulatory cytokine among all five of the currently recognized Breg cell subsets, several of which can be found in the affected brain hemisphere after induction of experimental stroke in mice. Transfer of enriched Breg cell subpopulations into both B-cell-depleted and wild-type mice confirmed their potent immunosuppressive activities in vivo, including recruitment and potentiation of regulatory T cells. Moreover, Breg cell therapy strongly reduced stroke volumes and treatment outcomes in ischaemic mice even when administered 24 hr after induction of experimental stroke, a treatment window far exceeding that of tPA. These striking results suggest that transfer of enriched Breg cell populations could have therapeutic value in human stroke, although considerable clinical challenges remain.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Suscetibilidade a Doenças , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Comunicação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Humanos , Acidente Vascular Cerebral/patologia
14.
J Neuroinflammation ; 15(1): 195, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970193

RESUMO

BACKGROUND: Stroke is the fifth leading cause of death and the leading cause of long-term disability in the USA, costing $40.2 billion in direct and indirect costs. Globally, stroke is the second leading cause of death and has a higher prevalence in lower- and middle-income countries compared to high-income countries. The role of the spleen in stroke has been studied in rodent models of stroke and is seen as a major contributor to increased secondary neural injury after stroke. Splenectomy 2 weeks prior to ischemic and hemorrhagic stroke in mice and rats shows decreased infarct volumes. Additionally, the spleen decreases in size following stroke in rodents. Pro-inflammatory mediators are also increased in the spleen and subsequently the brain after stroke. These data in preclinical models of stroke have led stroke neurologists to look at the splenic response in stroke subjects. The outcomes of these studies suggest the spleen is responding in a similar manner in stroke subjects as it is in animal models of stroke. CONCLUSION: Animal models demonstrating the detrimental role of the spleen in stroke are providing strong evidence of how the spleen is responding during stroke in human subjects. This indicates treatments targeting the splenic immune response in animals could provide useful targets and treatments for stroke subjects.


Assuntos
Baço/fisiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Ratos , Esplenectomia
15.
Metab Brain Dis ; 33(5): 1599-1607, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29916184

RESUMO

A seven day pretreatment course of an oral antibiotic cocktail (Ampicillin, Metronidazole, Neomycin Sulfate, and Vancomycin) was shown to induce changes in peripheral immune regulation and protect mice from signs of experimental autoimmune encephalomyelitis (EAE). To determine if a shorter course of antibiotic pretreatment could also protect the mice from EAE and induce regulatory immune cells, studies were conducted using the same oral antibiotic cocktail for three days. In addition, the CNS was examined to determine the effects of antibiotic pretreatment on EAE disease course and immune modulation within the affected tissue. The shorter three day pretreatment course was also significantly protective against severe EAE in C57BL/6 mice. Moreover, our study found increased frequencies of regulatory cells and a decrease in the frequency of anti-inflammatory macrophages in the spleen of EAE protected mice. Additionally, a chemokine and chemokine receptor array run on mRNA from spinal cords revealed that genes associated with regulatory T cells and macrophage recruitment were strongly upregulated in the antibiotic pretreated mice. Additional RT-PCR data showed genes associated with anti-inflammatory microglia/macrophages were upregulated and pro-inflammatory genes were downregulated. This suggests the macrophages recruited to the spinal cord by chemokines are subsequently polarized toward an anti-inflammatory phenotype. These results lend strong support to the conclusion that a three day course of antibiotic treatment given prior to the induction of severe EAE profoundly protected the mice by inducing regulatory lymphocytes in the periphery and an anti-inflammatory milieu in the affected spinal cord tissue.


Assuntos
Antibacterianos/farmacologia , Encefalomielite Autoimune Experimental/prevenção & controle , Imunomodulação , Macrófagos/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Quimiocinas/genética , Regulação para Baixo/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Receptores de Quimiocinas/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T Reguladores/imunologia , Regulação para Cima/genética
16.
J Neuroinflammation ; 14(1): 100, 2017 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-28477623

RESUMO

BACKGROUND: One of the main challenges in treating multiple sclerosis (MS) is reversing the effects of accumulated damage in the central nervous system (CNS) of progressive MS subjects. While most of the available drugs for MS subjects are anti-inflammatory and thus are limited to relapsing-remitting MS subjects, it is not clear to what extent their effects are capable of inducing axonal repair and remyelination in subjects with chronic MS. METHODS: A chronic model of experimental autoimmune encephalomyelitis (EAE) was used to evaluate the potency of partial MHC (pMHC) class II constructs in treating progressive EAE. RESULTS: We demonstrated an estrogen receptor alpha (ERα)-dependent increased dose requirement for effective treatment of female vs. male mice using pMHC. Such treatment using 100-µg doses of RTL342M or DRα1-mMOG-35-55 constructs significantly reversed clinical severity and showed a clear trend for inhibiting ongoing CNS damage, demyelination, and infiltration of inflammatory cells into the CNS in male mice. In contrast, WT female mice required larger 1-mg doses for effective treatment, although lower 100-µg doses were effective in ovariectomized or ERα-deficient mice with EAE. CONCLUSIONS: These findings will assist in the design of future clinical trials using pMHC for treatment of progressive MS.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Genes MHC da Classe II , Fármacos Neuroprotetores/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Caracteres Sexuais , Animais , Feminino , Genes MHC da Classe II/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Resultado do Tratamento
17.
J Neurosci Res ; 95(1-2): 437-446, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27870460

RESUMO

Ischemic stroke is a leading cause of death and disability in the United States. It is known that males and females respond differently to stroke. Depending on age, the incidence, prevalence, mortality rate, and disability outcome of stroke differ between the sexes. Females generally have strokes at older ages than males and, therefore, have a worse stroke outcome. There are also major differences in how the sexes respond to stroke at the cellular level. Immune response is a critical factor in determining the progress of neurodegeneration after stroke and is fundamentally different for males and females. Additionally, females respond to stroke therapies differently from males, yet they are often left out of the basic research that is focused on developing those therapies. With a resounding failure to translate stroke therapies from the bench to the bedside, it is clearer than ever that inclusion of both sexes in stroke studies is essential for future clinical success. This Mini-Review examines sex differences in the immune response to experimental stroke and its implications for therapy development. © 2016 Wiley Periodicals, Inc.


Assuntos
Sistema Imunitário , Caracteres Sexuais , Acidente Vascular Cerebral/imunologia , Pesquisa Translacional Biomédica , Envelhecimento , Animais , Modelos Animais de Doenças , Progressão da Doença , Hormônios Esteroides Gonadais/metabolismo , Humanos , Sistema Imunitário/patologia , Sistema Imunitário/fisiopatologia , Inflamação/etiologia , Acidente Vascular Cerebral/metabolismo
18.
Cell Immunol ; 318: 49-54, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28606360

RESUMO

Stroke is the leading cause of disability in the United States. Sex differences, including smaller infarcts in females and greater involvement of immune-mediated inflammation in males may affect the efficacy of immune-modulating interventions. To address these differences, we sought to identify distinct stroke-modifying mechanisms in female vs. male mice. The current study demonstrated smaller infarcts and increased levels of regulatory CD19+CD5+CD1dhi B10 cells as well as anti-inflammatory CD11b+CD206+ microglia/macrophages in the ipsilateral vs. contralateral hemisphere of female but not male mice undergoing 60min middle cerebral artery occlusion followed by 96h of reperfusion. Moreover, female mice with MCAO had increased total spleen cell numbers but lower B10 levels in spleens. These results elucidate differing sex-dependent regulatory mechanisms that account for diminished stroke severity in females and underscore the need to test immune-modulating therapies for stroke in both males and females.


Assuntos
Linfócitos B Reguladores/imunologia , Encéfalo/imunologia , Macrófagos/imunologia , Sexo , Acidente Vascular Cerebral/imunologia , Animais , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média/cirurgia , Fatores Sexuais
19.
Metab Brain Dis ; 32(5): 1747-1754, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28689297

RESUMO

Autoimmune diseases including multiple sclerosis predominantly affect females. Although high levels of sex hormones, particularly estrogen (E2), can reduce proinflammatory immune responses, it remains unclear if a lack of endogenous sex hormones might affect treatment with exogenous sex hormones. Pretreatment with E2 almost completely prevents intact female and male mice from developing clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) by promoting various regulatory immune cell phenotypes. To evaluate the effects of exogenous estrogen in the absence of endogenous sex hormones, the current study compared EAE severity and the emergence of different immunoregulatory cell populations after E2 pretreatment of ovariectomized (OVX) female versus male mice. We found that E2 equally protected both OVX females and males from EAE over a 21 day observation period concomitant with reduced total cell numbers in spleen and spinal cord (males only), but enhanced percentages of CD19+CD5+CD1dhi, CD19+CD138+CD44hi and CD19+Tim-1+ Breg cells, CD8+CD122+ Treg cells and CD11b+CD 206+ARG-1+ anti-inflammatory M2-like monocytes/macrophages in both groups. In contrast, E2 decreased the percentage of CD4+CD25+FoxP3+ Treg cells in OVX females but increased these Treg cells in males and intact female mice. These data suggest that with the exception of CD4+CD25+FoxP3+ Treg cells, E2 protection against EAE promotes highly overlapping immunoregulatory subsets in OVX females and males.


Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Estradiol/uso terapêutico , Animais , Antígenos CD/metabolismo , Linfócitos B Reguladores/metabolismo , Encefalomielite Autoimune Experimental/patologia , Estradiol/metabolismo , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Medula Espinal/patologia , Baço/patologia , Linfócitos T Reguladores
20.
Metab Brain Dis ; 32(5): 1395-1402, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28303450

RESUMO

Traumatic brain injury (TBI) results in severe neurological impairments without effective treatments. Inflammation appears to be an important contributor to key pathogenic events such as secondary brain injury following TBI and therefore serves as a promising target for novel therapies. We have recently demonstrated the ability of a molecular construct comprised of the human leukocyte antigen (HLA)-DRα1 domain linked covalently to mouse (m)MOG-35-55 peptide (DRα1-MOG-35-55 construct) to reduce CNS inflammation and tissue injury in animal models of multiple sclerosis and ischemic stroke. The aim of the current study was to determine if DRα1-MOG-35-55 treatment of a fluid percussion injury (FPI) mouse model of TBI could reduce the lesion size and improve disease outcome measures. Neurodeficits, lesion size, and immune responses were determined to evaluate the therapeutic potential and mechanisms of neuroprotection induced by DRα1-MOG-35-55 treatment. The results demonstrated that daily injections of DRα1-MOG-35-55 given after FPI significantly reduced numbers of infiltrating CD74+ and CD86+ macrophages and increased numbers of CD206+ microglia in the brain concomitant with smaller lesion sizes and improvement in neurodeficits. Conversely, DRα1-MOG-35-55 treatment of TBI increased numbers of circulating CD11b+ monocytes and their expression of CD74 but had no detectable effect on cell numbers or marker expression in the spleen. These results demonstrate that DRα1-MOG-35-55 therapy can reduce CNS inflammation and significantly improve histological and clinical outcomes after TBI. Future studies will further examine the potential of DRα1-MOG-35-55 for treatment of TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Antígenos de Diferenciação de Linfócitos B/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Antígeno CD11b/metabolismo , Clonagem Molecular , Antígenos de Histocompatibilidade Classe II/metabolismo , Contagem de Leucócitos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Doenças do Sistema Nervoso/etiologia , Fármacos Neuroprotetores/síntese química , Proteínas Recombinantes de Fusão/síntese química , Resultado do Tratamento
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