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1.
J Immunol ; 204(3): 531-539, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31852750

RESUMO

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R-/- mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R-/- mice correlates with increased numbers of GM-CSF+ CD4+ T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R-/- mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4+ T cells through the modulation of DCs.


Assuntos
Sistema Nervoso Central/fisiologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-9/metabolismo , Esclerose Múltipla/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Autoimunidade , Células Cultivadas , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-9/genética
2.
J Autoimmun ; 114: 102505, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32595012

RESUMO

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory conditions where inflammatory CD4+ T cells play a major role. Forkhead box P3 (Foxp3)+ regulatory T (Treg) cells suppress inflammation and an increase in their numbers and activity is beneficial for MS and EAE. However, studies have shown that Treg cells can transdifferentiate to pathogenic Th17 cells under inflammatory conditions. Drugs that stimulate Treg cell induction and their resistance to inflammatory stimuli are necessary to develop effective therapies to treat MS. Here, we show that primaquine (PQ), an anti-malarial drug, suppresses EAE through the stimulation of Foxp3+ Treg cells. PQ-elicited Treg cells are refractory to inflammatory stimuli and suppress EAE. Additionally, PQ-elicited Foxp3+ Treg cells were more efficient in suppressing the proliferation of responder cells compared to PBS-elicited Treg cells. Although PQ does not directly induce Foxp3+ Treg cell differentiation from naïve T cells, it modulated dendritic cells (DCs) to induce Foxp3+ Treg cells in an indoleamine 2,3 dioxygenase (IDO)-dependent manner. Together, our results show that PQ elicits Foxp3+ Treg cells with a superior suppressive activity to reduce EAE. PQ has the potential as a safe and effective treatment for MS and other CNS autoimmune inflammatory diseases.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Primaquina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Antimaláricos/farmacologia , Autoimunidade , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Ativação Linfocitária/imunologia , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
3.
Eur J Immunol ; 48(7): 1228-1234, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29572810

RESUMO

MS and EAE are T cell-driven autoimmune diseases of the CNS where IL-17-producing Th17 cells promote damage and are pathogenic. Conversely, tolerogenic DCs induce Treg cells and suppress Th17 cells. Chloroquine (CQ) suppresses EAE through the modulation of DCs by unknown mechanisms. Here, we show that STAT 1 is necessary for CQ-induced tolerogenic DCs (tolDCs) to efficiently suppress EAE. We observed that CQ induces phosphorylation of STAT1 in DCs in vivo and in vitro. Genetic blockage of STAT1 abrogated the suppressive activity of CQ-treated DCs. Opposed to its WT counterparts, CQ-treated STAT1-/- BMDCs were unable to suppress Th17 cells and increased EAE severity. Our findings show that STAT1 is a major signaling pathway in CQ-induced tolDCs and may shed light on new therapeutic avenues for the induction of tolDCs in autoimmune diseases such as MS.


Assuntos
Cloroquina/metabolismo , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Neutrófilos/imunologia , Fator de Transcrição STAT1/metabolismo , Células Th17/imunologia , Animais , Autoantígenos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Fator de Transcrição STAT1/genética , Transdução de Sinais
4.
J Neuroinflammation ; 16(1): 149, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324254

RESUMO

BACKGROUND: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. METHODS: We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. RESULTS: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. CONCLUSIONS: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Quinazolinonas/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas de Ligação a RNA/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/imunologia
5.
Brain Behav Immun ; 65: 173-182, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28476558

RESUMO

Neuromyelitis optica spectrum disorder is primarily an anti-aquaporin 4 autoantibody-mediated, central nervous system-restricted channelopathy. Patients frequently develop central nervous system-restricted lesions even though autoantigen aquaporin 4 in neuromyelitis optica spectrum disorder is broadly distributed in the central nervous system and peripheral organs. The cause of such tissue-specific immune response remains largely unknown. We confirmed here that CD59, an inhibitory regulator of the complement membrane attack complex, is expressed and co-localized with aquaporin 4 in peripheral organs but is only minimally expressed in astrocytes in the central nervous system. In addition, we further found that CD59 overexpression in mouse brains decreased demyelination, blocked the loss of astrocytes and aquaporin 4, and inhibited membrane attack complex formation and infiltration of inflammatory cells. Inactivation of CD59 in mouse peripheral aquaporin 4-expressing cells and tissues led to complement-dependent cytotoxicity. In accordance with the mouse data, human samples presented higher expression of CD59 in many aquaporin 4-expressing peripheral tissues but not in astrocytes. Silencing or blocking CD59 in aquaporin 4-expressing human tracheal epithelial and skeletal muscle cells induced membrane attack complex formation and cytotoxicity, which suggests a protective role of CD59 in anti-aquaporin 4 antibodies-mediated complement toxicity. Our findings suggest that low CD59 expression in astrocytes may contribute to central nervous system-restricted lesions in neuromyelitis optica spectrum disorder. Restoring CD59 expression in astrocytes may serve as a novel therapeutic target of neuromyelitis optica spectrum disorder.


Assuntos
Astrócitos/imunologia , Antígenos CD59/metabolismo , Animais , Aquaporina 4/imunologia , Aquaporina 4/metabolismo , Autoanticorpos , Autoimunidade/imunologia , Autoimunidade/fisiologia , Antígenos CD59/genética , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento , Proteínas do Sistema Complemento/imunologia , Feminino , Humanos , Imunidade Humoral/imunologia , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuromielite Óptica/imunologia , Neuromielite Óptica/metabolismo
6.
BMC Infect Dis ; 16: 209, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27189089

RESUMO

BACKGROUND: Paracoccidioidomycosis, a chronic granulomatous fungal disease caused by Paracoccidioides brasiliensis yeast cells affects mainly rural workers, albeit recently cases in immunosuppressed individuals has been reported. Protective immune response against P. brasiliensis is dependent on the activity of helper T cells especially IFN-γ-producing Th1 cells. It has been proposed that Paracoccidioides brasiliensis is able to modulate the immune response towards a permissive state and that the thymus plays a major role in it. METHODS: In this paper, we show that acute infection of BALB/c mice with P. brasiliensis virulent isolate (Pb18) might cause alterations in the thymic environment as well as the prohibitive TCR-expressing T cells in the spleens. RESULTS: After seven days of infection, we found yeast cells on the thymic stroma, the thymic epithelial cells (TEC) were altered regarding their spatial-orientation and inflammatory mediators gene expression was increased. Likewise, thymocytes (differentiating T cells) presented higher migratory ability in ex vivo experiments. Notwithstanding, P. brasiliensis-infected mice showed an increased frequency of prohibitive TCR-expressing T cells in the spleens, suggesting that the selection processes that occur in the thymus may be compromised during the acute infection. CONCLUSION: In this paper, for the first time, we show that acute infection with Paracoccidioides brasiliensis yeast cells promotes thymic alterations leading to a defective repertoire of peripheral T cells. The data presented here may represent new mechanisms by which P. brasiliensis subverts the immune response towards the chronic infection observed in humans.


Assuntos
Paracoccidioides/fisiologia , Paracoccidioidomicose/imunologia , Receptores de Antígenos de Linfócitos T/genética , Timo/microbiologia , Animais , Humanos , Ativação Linfocitária , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Paracoccidioidomicose/genética , Paracoccidioidomicose/microbiologia , Receptores de Antígenos de Linfócitos T/imunologia , Baço/imunologia , Células Th1/imunologia , Timo/imunologia
7.
Immunology ; 146(3): 486-95, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26302057

RESUMO

Paracoccidioidomycosis is a systemic infection prevalent in Latin American countries. Disease develops after inhalation of Paracoccidioides brasiliensis conidia followed by an improper immune activation by the host leucocytes. Dendritic cells (DCs) are antigen-presenting cells with the unique ability to direct the adaptive immune response by the time of activation of naive T cells. This study was conducted to test whether extracts of P. brasiliensis would induce maturation of DCs. We found that DCs treated with extracts acquired an inflammatory phenotype and upon adoptive transfer conferred protection to infection. Interestingly, interleukin-10 production by CD8(+) T cells was ablated following DC transfer. Further analyses showed that lymphocytes from infected mice were high producers of interleukin-10, with CD8(+) T cells being the main source. Blockage of cross-presentation to CD8(+) T cells by modulated DCs abolished the protective effect of adoptive transfer. Collectively, our data show that adoptive transfer of P. brasiliensis-modulated DCs is an interesting approach for the control of infection in paracoccidioidomycosis.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Interleucina-10/biossíntese , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/prevenção & controle , Transferência Adotiva , Animais , Antígenos de Fungos/farmacologia , Diferenciação Celular/imunologia , Apresentação Cruzada , Citocinas/biossíntese , Células Dendríticas/citologia , Células Dendríticas/microbiologia , Feminino , Vacinas Fúngicas/imunologia , Vacinas Fúngicas/farmacologia , Mediadores da Inflamação/metabolismo , Interleucina-10/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Immunology ; 143(2): 164-73, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24689455

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells specifically targeted during Plasmodium infection. Upon infection, DCs show impaired antigen presentation and T-cell activation abilities. In this study, we aimed to evaluate whether cellular extracts obtained from Plasmodium berghei-infected erythrocytes (PbX) modulate DCs phenotypically and functionally and the potential therapeutic usage of PbX-modulated DCs in the control of experimental autoimmune encephalomyelitis (EAE, the mouse model for human multiple sclerosis). We found that PbX-treated DCs have impaired maturation and stimulated the generation of regulatory T cells when cultured with naive T lymphocytes in vitro. When adoptively transferred to C57BL/6 mice the EAE severity was reduced. Disease amelioration correlated with a diminished infiltration of cytokine-producing T cells in the central nervous system as well as the suppression of encephalitogenic T cells. Our study shows that extracts obtained from P. berghei-infected erythrocytes modulate DCs towards an immunosuppressive phenotype. In addition, the adoptive transfer of PbX-modulated DCs was able to ameliorate EAE development through the suppression of specific cellular immune responses towards neuro-antigens. To our knowledge, this is the first study to present evidence that DCs treated with P. berghei extracts are able to control autoimmune neuroinflammation.


Assuntos
Transferência Adotiva , Células Dendríticas/transplante , Terapia de Imunossupressão/métodos , Neurite Autoimune Experimental/prevenção & controle , Plasmodium berghei/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/parasitologia , Feminino , Imunidade Celular , Camundongos , Camundongos Endogâmicos C57BL , Neurite Autoimune Experimental/imunologia , Neurite Autoimune Experimental/metabolismo , Neurite Autoimune Experimental/parasitologia , Fenótipo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/parasitologia , Fatores de Tempo
9.
Immunol Cell Biol ; 92(2): 124-32, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24217811

RESUMO

Chloroquine (CQ), an antimalarial drug, has been shown to modulate the immune system and reduce the severity of experimental autoimmune encephalomyelitis (EAE). The mechanisms of disease suppression are dependent on regulatory T cell induction, although Tregs-independent mechanisms exist. We aimed to evaluate whether CQ is capable to modulate bone marrow-derived dendritic cells (DCs) both phenotypically and functionally as well as whether transfer of CQ-modulated DCs reduces EAE course. Our results show that CQ-treated DCs presented altered ultrastructure morphology and lower expression of molecules involved in antigen presentation. Consequently, T cell proliferation was diminished in coculture experiments. When transferred into EAE mice, DC-CQ was able to reduce the clinical manifestation of the disease through the modulation of the immune response against neuroantigens. The data presented herein indicate that chloroquine-mediated modulation of the immune system is achieved by a direct effect on DCs and that DC-CQ adoptive transfer may be a promising approach for avoiding drug toxicity.


Assuntos
Transferência Adotiva , Apresentação de Antígeno/efeitos dos fármacos , Antirreumáticos/farmacologia , Cloroquina/farmacologia , Células Dendríticas , Encefalomielite Autoimune Experimental/terapia , Animais , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Linfócitos T/imunologia , Linfócitos T/patologia
10.
Cell Immunol ; 280(1): 113-23, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23298866

RESUMO

Dietary proteins play an important role in the regulation of systemic immune response, in a phenomenon known as oral tolerance (OT). To evaluate the effects of OT on a murine model of type II collagen (CII) plus ovalbumin (OVA)-induced arthritis (CIA), mice were fed with OVA either before or after CIA induction. OT significantly reduced the paw edema and synovial inflammation, as well as serum levels of anti-CII, the ex vivo proliferation and inflammatory cytokine production by spleen cells from CIA mice. The frequencies of Foxp3(+) and IL-10(+) cells were higher, whereas IFNγ(+) cells and IL-17(+) cells were lower, among gated CD4(+) spleen T cells from tolerized CIA mice than in those from non-tolerized CIA mice. Adoptive transfer of tolerogenic dendritic cells (DCs) before CIA induction mimics the effects observed in the OT. We demonstrate here that bystander suppression induced by OT can modify the course of CIA and tolerogenic DCs play a role this phenomenon.


Assuntos
Artrite Experimental/terapia , Proteínas Alimentares/uso terapêutico , Tolerância Imunológica , Ovalbumina/uso terapêutico , Transferência Adotiva , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Experimental/prevenção & controle , Efeito Espectador , Técnicas de Cocultura , Colágeno Tipo II/imunologia , Colágeno Tipo II/toxicidade , Citocinas/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/transplante , Proteínas Alimentares/imunologia , Edema/etiologia , Fatores de Transcrição Forkhead/análise , Imunização , Interferon gama , Interleucina-10 , Interleucina-17 , Isoanticorpos/sangue , Isoanticorpos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Ovalbumina/toxicidade , Organismos Livres de Patógenos Específicos , Baço/imunologia , Baço/patologia
11.
J Clin Invest ; 132(22)2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36136587

RESUMO

Astrocytes are highly heterogeneous in their phenotype and function, which contributes to CNS disease, repair, and aging; however, the molecular mechanism of their functional states remains largely unknown. Here, we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, played an important role in the detrimental actions of reactive astrocytes, whereas its inactivation conferred these cells with antiinflammatory functions that inhibited the production of proinflammatory mediators by myeloid cells and microglia and promoted the differentiation of oligodendrocyte progenitor cells. Mice with astrocyte-specific Sirt1 knockout (Sirt1-/-) had suppressed progression of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammatory demyelinating disease. Ongoing EAE was also suppressed when Sirt1 expression in astrocytes was diminished by a CRISPR/Cas vector, resulting in reduced demyelination, decreased numbers of T cells, and an increased rate of IL-10-producing macrophages and microglia in the CNS, whereas the peripheral immune response remained unaffected. Mechanistically, Sirt1-/- astrocytes expressed a range of nuclear factor erythroid-derived 2-like 2 (Nfe2l2) target genes, and Nfe2l2 deficiency shifted the beneficial action of Sirt1-/- astrocytes to a detrimental one. These findings identify an approach for switching the functional state of reactive astrocytes that will facilitate the development of astrocyte-targeting therapies for inflammatory neurodegenerative diseases such as multiple sclerosis.


Assuntos
Astrócitos , Encefalomielite Autoimune Experimental , Sirtuína 1 , Animais , Camundongos , Astrócitos/enzimologia , Astrócitos/patologia , Autoimunidade , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Camundongos Endogâmicos C57BL , Fenótipo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Camundongos Knockout
12.
J Clin Transl Res ; 7(1): 22-33, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-34104806

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a disease of the central nervous system where an autoimmune response leads to chronic inflammation. It represents the second leading cause of non-traumatic disability in the world, affecting mainly young adults and with high female to male incidence. At present, the causative agent in MS is unknown, preventing the development of prophylaxis policies and the understanding of how the human system copes with this complex inflammation. Tetracyclines (Tet) have attracted great attention due to their anti-inflammatory effects. Minocycline and doxycycline represent the second-generation Tet that have been largely used to treat acne and to suppress inflammation. In addition, they are safer and cheaper than other drugs currently used to treat MS. AIM: This study aims to review recent data involving the Tet minocycline and doxycycline and their therapeutic potential in MS. RELEVANCE FOR PATIENTS: Many of the drugs used to treat MS have severe side effects and are costly. Tet, on the other hand, are a safe and inexpensive class of drugs that can modulate the immune response in MS patients.

13.
Peptides ; 146: 170648, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34537257

RESUMO

Peptides are molecules that have emerged as crucial candidates for the development of anticancer drugs. Spider venoms are a rich source of peptides (venom peptides - VPs) with biological effects. VPs have been tested as adjuvants in the activation of cells of the immune system with the aim of improving immunotherapies for the treatment of neoplasms. In the present study, the effects of SNX-482, a peptide from the African tarantula Hysterocrates gigas, on macrophages were described. The results showed that the peptide activated M0-macrophages, increasing costimulatory molecules (CD40, CD68, CD80, CD83, CD86) involved in antigen presentation, and also augmenting the checkpoint molecules PD-L1, CTLA-4 and FAS-L; these effects were not concentration-dependent. SNX-482 also increased the release of IL-23 and upregulated the expression of ccr4, ifn-g, gzmb and pdcd1, genes important for the anticancer response. The pretreatment of macrophages with the peptide did not interfere in the modulation of T cells, and macrophages previously polarized to M1 and M2 profile did not respond to SNX-482. These findings represent the expansion of knowledge about the use of VPs in drug discovery, pointing to a potential new candidate for anticancer immunotherapy. Considering that most immunotherapies target the adaptive system, the modulation of macrophages (an innate immune cell) by SNX-482 is especially relevant.


Assuntos
Adjuvantes Imunológicos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Venenos de Aranha/química , Aranhas/química , Animais , Antígenos CD/imunologia , Linhagem Celular Tumoral , Polaridade Celular , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Ativação de Macrófagos/imunologia , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Venenos de Aranha/farmacologia
14.
Front Immunol ; 12: 679498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149716

RESUMO

IFN-ß has been the treatment for multiple sclerosis (MS) for almost three decades, but understanding the mechanisms underlying its beneficial effects remains incomplete. We have shown that MS patients have increased numbers of GM-CSF+ Th cells in circulation, and that IFN-ß therapy reduces their numbers. GM-CSF expression by myelin-specific Th cells is essential for the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These findings suggested that IFN-ß therapy may function via suppression of GM-CSF production by Th cells. In the current study, we elucidated a feedback loop between monocytes and Th cells that amplifies autoimmune neuroinflammation, and found that IFN-ß therapy ameliorates central nervous system (CNS) autoimmunity by inhibiting this proinflammatory loop. IFN-ß suppressed GM-CSF production in Th cells indirectly by acting on monocytes, and IFN-ß signaling in monocytes was required for EAE suppression. IFN-ß increased IL-10 expression by monocytes, and IL-10 was required for the suppressive effects of IFN-ß. IFN-ß treatment suppressed IL-1ß expression by monocytes in the CNS of mice with EAE. GM-CSF from Th cells induced IL-1ß production by monocytes, and, in a positive feedback loop, IL-1ß augmented GM-CSF production by Th cells. In addition to GM-CSF, TNF and FASL expression by Th cells was also necessary for IL-1ß production by monocyte. IFN-ß inhibited GM-CSF, TNF, and FASL expression by Th cells to suppress IL-1ß secretion by monocytes. Overall, our study describes a positive feedback loop involving several Th cell- and monocyte-derived molecules, and IFN-ß actions on monocytes disrupting this proinflammatory loop.


Assuntos
Autoimunidade , Comunicação Celular , Interferon beta/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoimunidade/efeitos dos fármacos , Comunicação Celular/genética , Comunicação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interferon beta/farmacologia , Camundongos , Camundongos Knockout , Monócitos/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos
15.
J Biochem ; 170(1): 51-68, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-33599263

RESUMO

Immunomodulation has been considered an important approach in the treatment of malignant tumours. However, the modulation of innate immune cells remains an underexplored tool. Studies from our group demonstrated that the Phoneutria nigriventer spider venom (PnV) administration increased the infiltration of macrophage in glioblastoma, in addition to decreasing the tumour size in a preclinical model. The hypothesis that PnV would be modulating the innate immune system led us to the main objective of the present study: to elucidate the effects of PnV and its purified fractions on cultured macrophages. Results showed that PnV and the three fractions activated macrophages differentiated from bone marrow precursors. Further purification generated 23 subfractions named low weight (LW-1 to LW-12) and high weight (HW-1 to HW-11). LW-9 presented the best immunomodulatory effect. Treated cells were more phagocytic, migrated more, showed an activated morphological profile and induced an increased cytotoxic effect of macrophages on tumour cells. However, while M1-controls (LPS) increased IL-10, TNF-alpha and IL-6 release, PnV, fractions and subfractions did not alter any cytokine, with the exception of LW-9 that stimulated IL-10 production. These findings suggest that molecules present in LW-9 have the potential to be used as immunoadjuvants in the treatment of cancer.


Assuntos
Adjuvantes Imunológicos/farmacologia , Glioblastoma/terapia , Imunoterapia , Macrófagos/efeitos dos fármacos , Venenos de Aranha/farmacologia , Animais , Células Cultivadas , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos
16.
Artigo em Inglês | MEDLINE | ID: mdl-32371548

RESUMO

OBJECTIVE: To study the immunomodulatory effect of dimethyl fumarate (DF) on granulocyte macrophage colony-stimulating factor (GM-CSF) production in CD4+ T cells in experimental autoimmune encephalomyelitis (EAE) and human peripheral blood mononuclear cells (PBMCs). METHODS: We collected splenocytes and CD4+ T cells from C57BL/6 wild-type and interferon (IFN)-γ-deficient mice. For human PBMCs, venous blood was collected from healthy donors, and PBMCs were collected using the Percoll gradient method. Cells were cultured with anti-CD3/28 in the presence/absence of DF for 3 to 5 days. Cells were stained and analyzed by flow cytometry. Cytokines were measured by ELISA in cell supernatants. For in vivo experiments, EAE was induced by myelin oligodendrocyte glycoprotein35-55 and mice were treated with oral DF or vehicle daily. RESULTS: DF acts directly on CD4+ T cells and suppresses GM-CSF-producing Th1 not Th17 or single GM-CSF+ T cells in EAE. In addition, GM-CSF suppression depends on the IFN-γ pathway. We also show that DF specifically suppresses Th1 and GM-CSF-producing Th1 cells in PBMCs from healthy donors. CONCLUSIONS: We suggest that DF exclusively suppresses GM-CSF-producing Th1 cells in both animal and human CD4+ T cells through an IFN-γ-dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Granulócitos/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interferon gama/metabolismo , Fator Estimulador de Colônias de Macrófagos/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Adulto , Animais , Fumarato de Dimetilo/administração & dosagem , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Interferon gama/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
17.
Immunobiology ; 225(4): 151963, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32747019

RESUMO

Studies that show an overview of the peripheral immune response in a model of Paracoccidioides brasiliensis (Pb) infection in females are scarce in the literature. We sought to characterize the innate and adaptive immune responses in female C57BL/6 mice infected with Pb through two distinct routes of administration, intranasal and intravenous. In addition to the lung, P. brasiliensis yeast cells were observed in liver and brain tissues of females infected intravenously. To our knowledge, our study is the first to prove the presence of this pathogenic fungus in the cerebral cortex of female mice. During the initial stages of infection, augmented expression of both MHCII and CD86 was observed on the surface of CD11c+ pulmonary antigen-presenting cells (APCs) in intranasally and intravenously infected females. However, CD40 expression was downregulated in these cells. Concomitantly with increasing serum IL-10 levels, we noted that splenic dendritic cells (DCs) from both intravenously- and intranasally-infected female mice had acquired an immature phenotype. Further, increased T regulatory cell counts were observed in female mice infected via both routes, along with an increase in the infiltration of IL-10-producing CD8+ T cells into the lungs. Moreover, we noted that P. brasiliensis infection resulted in enhanced IL-10 production - by CD11c+ APCs in the lung tissue - and induction of Th17 polarization. Taken together, our results suggest that P. brasiliensis could modulates the immune response in female mice by influencing the balance between regulatory T cells (Tregs) and Th17 polarization.


Assuntos
Interações Hospedeiro-Patógeno , Contagem de Linfócitos , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Citocinas/metabolismo , Feminino , Interações Hospedeiro-Patógeno/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Paracoccidioidomicose/transmissão , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
18.
Brain Sci ; 10(6)2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32516999

RESUMO

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory diseases of the central nervous system (CNS), where leukocytes and CNS resident cells play important roles in disease development and pathogenesis. The antimalarial drug chloroquine (CQ) has been shown to suppress EAE by modulating dendritic cells (DCs) and Th17 cells. However, the mechanism of action by which CQ modulates EAE is far from being elucidated. Here, we comprehensively analyzed the CNS of CQ and PBS-treated EAE mice to identify and characterize the cells that are affected by CQ. Our results show that leukocytes are largely modulated by CQ and have a reduction in the expression of inflammatory markers. Intriguingly, CQ vastly modulated the CNS resident cells astrocytes, oligodendrocytes (OLs) and microglia (MG), with the latter producing IL-10 and IL-12p70. Overall, our results show a panoramic view of the cellular components that are affect by CQ and provide further evidence that drug repurposing of CQ will be beneficial to MS patients.

19.
Front Immunol ; 11: 576752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193372

RESUMO

Antigen (Ag)-specific tolerance induction by intravenous (i. v.) injection of high-dose auto-Ags has been explored for therapy of autoimmune diseases, including multiple sclerosis (MS). It is thought that the advantage of such Ag-specific therapy over non-specific immunomodulatory treatments would be selective suppression of a pathogenic immune response without impairing systemic immunity, thus avoiding adverse effects of immunosuppression. Auto-Ag i.v. tolerance induction has been extensively studied in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and limited clinical trials demonstrated that it is safe and beneficial to a subset of MS patients. Nonetheless, the mechanisms of i.v. tolerance induction are incompletely understood, hampering the development of better approaches and their clinical application. Here, we describe a pathway whereby auto-Ag i.v. injected into mice with ongoing clinical EAE induces interferon-gamma (IFN-γ) secretion by auto-Ag-specific CD4+ T cells, triggering interleukin (IL)-27 production by conventional dendritic cells type 1 (cDC1). IL-27 then, via signal transducer and activator of transcription 3 activation, induces programmed death ligand 1 (PD-L1) expression by monocyte-derived dendritic cells (moDCs) in the central nervous system of mice with EAE. PD-L1 interaction with programmed cell death protein 1 on pathogenic CD4+ T cells leads to their apoptosis/anergy, resulting in disease amelioration. These findings identify a key role of the IFN-γ/IL-27/PD-L1 axis, involving T cells/cDC1/moDCs in the induction of i.v. tolerance.


Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Sistema Nervoso Central/imunologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Monócitos/imunologia , Esclerose Múltipla/imunologia , Animais , Autoimunidade , Antígeno B7-H1/genética , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Interleucina-27/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Front Immunol ; 11: 569530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101289

RESUMO

Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, suppresses experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), by inducing the production of immunomodulatory molecules, e.g., IL-10. In an effort to find the upstream pathway(s) of the mechanism underlying these effects, we have tested certain upregulated immunomodulatory molecules. Among them, we found increased levels of IL-27 and IFN-ß, one of the first-line MS therapies. Indeed, while low levels of IFN-ß production in sera and type I interferon receptor (IFNAR1) expression in spinal cord of saline-treated control EAE mice were detected, they were significantly increased after MAT treatment. Increased numbers of CD11b+IFN-ß+ microglia/infiltrating macrophages were observed in the CNS of MAT-treated mice. The key role of IFN-ß induction in the suppressive effect of MAT on EAE was further verified by administration of anti-IFN-ß neutralizing antibody, which largely reversed the therapeutic effect of MAT. Further, we found that, while MAT treatment induced production of IL-27 and IL-10 by CNS microglia/macrophages, this effect was significantly reduced by IFN-ß neutralizing antibody. Finally, the role of IFN-ß in MAT-induced IL-27 and IL-10 production was further confirmed in human monocytes in vitro. Together, our study demonstrates that MAT exerts its therapeutic effect in EAE through an IFN-ß/IL-27/IL-10 pathway, and is likely a novel, safe, low-cost, and effective therapy as an alternative to exogenous IFN-ß for MS.


Assuntos
Alcaloides/farmacologia , Autoimunidade/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Interferon beta/metabolismo , Quinolizinas/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental , Feminino , Imunofluorescência , Humanos , Interferon beta/antagonistas & inibidores , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Índice de Gravidade de Doença , Matrinas
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