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1.
Biomol Concepts ; 15(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38242137

RESUMO

In the past two decades, oxidative stress (OS) has drawn a lot of interest due to the revelation that individuals with many persistent disorders including diabetes, polycystic ovarian syndrome (PCOS), cardiovascular, and other disorders often have aberrant oxidation statuses. OS has a close interplay with PCOS features such as insulin resistance, hyperandrogenism, and chronic inflammation; there is a belief that OS might contribute to the development of PCOS. PCOS is currently recognized as not only one of the most prevalent endocrine disorders but also a significant contributor to female infertility, affecting a considerable proportion of women globally. Therefore, the understanding of the relationship between OS and PCOS is crucial to the development of therapeutic and preventive strategies for PCOS. Moreover, the mechanistic study of intracellular reactive oxygen species/ reactive nitrogen species formation and its possible interaction with women's reproductive health is required, which includes complex enzymatic and non-enzymatic antioxidant systems. Apart from that, our current review includes possible regulation of the pathogenesis of OS. A change in lifestyle, including physical activity, various supplements that boost antioxidant levels, particularly vitamins, and the usage of medicinal herbs, is thought to be the best way to combat this occurrence of OS and improve the pathophysiologic conditions associated with PCOS.


Assuntos
Hiperandrogenismo , Resistência à Insulina , Síndrome do Ovário Policístico , Feminino , Humanos , Síndrome do Ovário Policístico/terapia , Síndrome do Ovário Policístico/complicações , Antioxidantes/uso terapêutico , Hiperandrogenismo/complicações , Estresse Oxidativo
2.
Cell Mol Neurobiol ; 44(1): 2, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38099973

RESUMO

Coronavirus disease 2019 (COVID-19) is primarily a respiratory disease causing a worldwide pandemic in the year of 2019. SARS-CoV-2 is an enveloped, positive-stranded RNA virus that could invade the host through spike protein and exhibits multi-organ effects. The Brain was considered to be a potential target for SARS-CoV-2 infection. Although neuropsychiatric symptoms and cognitive impairments were observed in COVID-19 patients even after recovery the mechanism of action is not well documented. In this review, the contribution of microglia in response to SARS-CoV-2 infection was discussed aiming to design a therapeutic regimen for the management of neuroinflammation and psycho-behavioral alterations. Priming of microglia facilitates the hyper-activation state when it interacts with SARS-CoV-2 known as the 'second hit'. Moreover, the microgliosis produces reactive free radicals and pro-inflammatory cytokines like IL-1ß, IFN-γ, and IL-6 which ultimately contribute to a 'cytokine storm', thereby increasing the occurrence of cognitive and neurological dysfunction. It was reported that elevated CCL11 may be responsible for psychiatric disorders and ROS/RNS-induced oxidative stress could promote major depressive disorder (MDD) and phenotypic switching. Additionally, during SARS-CoV-2 infection microglia-CD8+ T cell interaction may have a significant role in neuronal cell death. This cytokine-mediated cellular cross-talking plays a crucial role in pro-inflammatory and anti-inflammatory balance within the COVID-19 patient's brain. Therefore, all these aspects will be taken into consideration for developing novel therapeutic strategies to combat SARS-CoV-2-induced neuroinflammation.


Assuntos
COVID-19 , Transtorno Depressivo Maior , Humanos , SARS-CoV-2 , Microglia , Doenças Neuroinflamatórias , Citocinas
3.
J Appl Toxicol ; 43(10): 1549-1572, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37177863

RESUMO

Multi-organ dysfunction is one of the major reasons behind the high mortality of sepsis throughout the world. With the pathophysiology of sepsis remaining largely unknown, the uncontrolled reactive oxygen species (ROS) production along with the decreased antioxidants contributes to the progression toward septic shock. Being the effector cells of the innate immunity system, macrophages secrete both pro-inflammatory and anti-inflammatory mediators during inflammation. Lipopolysaccharide (LPS) binding to toll-like receptor 4 (TLR4) releases TNF-α, which initiates pro-inflammatory events through tumor necrosis factor receptor 1 (TNFR1) signaling. However, it is counteracted by the anti-inflammatory interleukin 10 (IL-10) causing decreased oxidative stress. Our study thus aimed to assess the effects of exogenous IL-10 treatment post-neutralization of TLR4 and TNFR1 (by anti-TLR4 antibody and anti-TNFR1 antibody, respectively) in an in vivo murine model of LPS-sepsis. We have also examined the tissue-specific antioxidant status in the spleen, liver, and lungs along with the serum cytokine levels in adult male Swiss albino mice to determine the functional association with the disease. The results showed that administration of recombinant IL-10 post-neutralization of the receptors was beneficial in shifting the macrophage polarization to the anti-inflammatory M2 phenotype. IL-10 treatment significantly downregulated the free radicals production resulting in diminished lipid peroxidase (LPO) levels. The increased antioxidant activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GRX ) conferred protection against LPS-induced sepsis. Western blot data further confirmed diminished expressions of TLR4 and TNFR1 along with suppressed stress-activated protein kinases/Jun amino-terminal kinases (SAPK/JNK) and increased SOD and CAT expressions, which altogether indicated that neutralization of TLR4 and TNFR1 along with IL-10 posttreatment might be a potential therapeutic measure for the treatment of sepsis.


Assuntos
Antioxidantes , Sepse , Masculino , Camundongos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Interleucina-10 , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos/toxicidade , Sepse/tratamento farmacológico , Sepse/metabolismo , Macrófagos , Fator de Necrose Tumoral alfa/metabolismo , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
4.
Scand J Immunol ; 97(6): e13252, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36597222

RESUMO

Septic arthritis is a joint disease caused by Staphylococcus aureus. Different macrophage populations contribute in various ways to control blood-borne infections and induce inflammatory responses. Macrophage tissue-resident niche is necessary for the suppression of chronic inflammation and may contribute to the pathogenesis of septic arthritis. Thus, to obtain a resolution of the disease and restoration of synovial homeostasis, it needs the activation of macrophages that further regulate the inflammatory consequences. The aim of this study was to find out the mechanism by which neutralization of transforming growth factor-beta (TGF-ß) and/or interleukin (IL)-6 after induction of septic arthritis could alter the specific macrophage responses in spleen and synovial joints via different cytokines (osteoprotegerin (OPG), osteopontin (OPN), IL-10, IL-12 and CXCL8) cross-talking, and how the response could be modulated by reactive oxygen species vs antioxidant enzyme activities. Dual neutralization of TGF-ß and IL-6 is notably effective in eliciting splenic and synovial tissue-resident macrophage responses. Synovial macrophage-derived IL-10 can elicit protection against septic arthritis via regulating receptor-activated nuclear factor Kappa-B ligand (RANKL)/OPG interaction. They also reduced oxidative stress by increasing the activity of antioxidant enzymes including SOD and catalase. Histopathological analysis revealed that dual neutralization of TGF-ß and IL-6 prevented bone destruction and osteoclastic activity in septic arthritis by promoting the differential functional response of the splenic and synovial macrophages. Additionally, the macrophage-derived IL-10 can elicit protection against S. aureus-induced septic arthritis via regulating RANKL/OPG interaction. Further studies on STAT3 and STAT4 are needed for the understanding of such cross-talking in resident macrophages of arthritic mice.


Assuntos
Artrite Infecciosa , Interleucina-10 , Animais , Camundongos , Staphylococcus aureus , Fator de Crescimento Transformador beta , Interleucina-6 , Baço/patologia , Antioxidantes , Inflamação , Artrite Infecciosa/patologia , Macrófagos/patologia
5.
Int Immunopharmacol ; 115: 109654, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36621328

RESUMO

Rheumatoid arthritis (RA) primarily affecting the synovial tissue, has emerged as a major concern leading to the pressing need to develop effective treatment strategies. In the affected synovial tissue, resident macrophages play a pivotal role in the pathogenesis of RA. TNF-α and IL-1ß released from pro-inflammatory M1 synovial macrophages are the master regulators of chronic joint inflammation. In this study collagen-induced rheumatoid arthritis model was developed in mice and post isolation, macrophages were subjected to administration with neutralizing antibodies IL1R and TNFR1 either alone or in combination. Flow cytometric analysis followed by Western blots, ROS, and IL-1ß, TNF-α release assays were performed. Outcomes suggested that post-dual blockade of IL1R and TNFR1 arthritic synovial macrophages showed a shifting of the M1 towards the anti-inflammatory M2 phenotype. Moreover, the switch towards the M2 phenotype might be responsible for decreased levels of IL-1ß,TNF-α, and ROS and simultaneous elevation in the activity of antioxidant enzymes like SOD, CAT, and GPX content in the isolated macrophages. Simultaneous blocking of both IL1R and TNFR1 also showed a sharp reduction in the expression of NF-κB and SAPK-JNK. The elevated arginase and GRX activity further confirmed the polarization towards M2. Moreover, bioinformatics analysis was performed,and it was found that blocking TNFR1 with an antibody could hamper the binding of TNF to TNFR1 in the TNF-TNFR1 pathway. Thus, it may be inferred that dual blockade of IL1R and TNFR1 and a suitable antibody blocking of TNFR1 might be alternative therapeutic approaches for the regulation of RA-induced inflammation in the future.


Assuntos
Artrite Reumatoide , Receptores Tipo I de Fatores de Necrose Tumoral , Animais , Camundongos , Anticorpos/farmacologia , Inflamação/metabolismo , Macrófagos , Espécies Reativas de Oxigênio/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo , Receptores de Interleucina-1/metabolismo
6.
Mol Immunol ; 152: 183-206, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371814

RESUMO

Septic arthritis is an inflammatory joint disease caused by S. aureus. Hematogenous entry of the bacteria to the synovium produces pro-inflammatory cytokines TGF-ß and IL-6, which alter the Th17/Treg balance. Hence, targeting TGF-ß and IL-6 could be beneficial in ameliorating arthritis. Antibody neutralization of TGF-ß and IL-6 to modulate Th17/Treg homeostasis and RANKL/OPG ratio are not investigated so far in S. aureus-induced septic arthritis. Contribution of synovial lymphocyte-derived cytokines IL-10, IL-12, and CXCL-8; along with OPN, OPG, CRP, cellular ROS, antioxidant enzymes, and the expressions of RANKL, SAPK-JNK, MMP2, SOD, CAT, GPx, TGF-ß and IL-6 were studied in lymphocytes of blood, spleen and synovial tissues of mice treated with antibody against of TGF-ß and IL-6 after induction of septic arthritis. Dual neutralization of TGF-ß and IL-6 is effective in shifting the Th17 cell into immunosuppressive Treg cell of the arthritic mice and enhances the RANKL/OPG interaction leading to the down-regulation of osteoclastic activity and reduces the production of OPN, IL-12, CXCL-8, and CRP. Additionally, it reduces oxidative stress via enhancing the activities of antioxidant enzymes including SOD, catalase, and GPx in lymphocytes. Thus it can be concluded that dual endogenous neutralization of TGF-ß and IL-6 may be chosen as an alternative therapeutic approach for controlling the severity of septic arthritis through Treg-derived IL-10 that could ameliorate the inflammatory consequences of septic arthritis via influencing RANKL/OPG interaction in lymphocytes.


Assuntos
Artrite Infecciosa , Interleucina-10 , Camundongos , Animais , Interleucina-10/metabolismo , Staphylococcus aureus , Fator de Crescimento Transformador beta , Interleucina-6 , Antioxidantes/farmacologia , Artrite Infecciosa/microbiologia , Células Th17 , Citocinas/metabolismo , Interleucina-12/farmacologia , Superóxido Dismutase
7.
Inflammopharmacology ; 30(4): 1303-1322, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35704229

RESUMO

Microglial inflammatory responses play a central role in the pathogenesis of S. aureus induced brain infections. Upon activation, microglia produces free radicals (ROS/RNS) and disrupts the cellular antioxidant defense to combat invading microorganisms. Despite conventional antibiotic or steroid therapy, microglial over-activation could not be controlled. So, an attempt had been taken by using a natural antioxidant ascorbic acid along with ciprofloxacin to regulate microglial over-activation by involving TLR-2 and glucocorticoid receptor (GR) in an in-vitro cell culture-based study. Combinatorial treatment during TLR-2 neutralization effectively reduced the bacterial burden at 60 min compared to the GR blocking condition (p < 0.05). Moreover, the infection-induced H2O2, O2.-, and NO release in microglial cell culture was diminished possibly by enhancing SOD and catalase activities in the same condition (p < 0.05). The arginase activity was markedly increased after TLR-2 blocking in the combinatorial group compared to single treatments (p < 0.05). Experimental results indicated that combinatorial treatment may act through up-regulating GR expression by augmenting endogenous corticosterone levels. However, better bacterial clearance could further suppress the TLR-2 mediated pro-inflammatory NF-κB signaling. From Western blot analysis, it was concluded that ciprofloxacin-ascorbic acid combination in presence of anti-TLR-2 antibody exhibited 81.25% inhibition of TLR-2 expression while the inhibition for GR was 3.57% with respect to the infected group. Therefore, during TLR-2 blockade ascorbic acid combination might be responsible for the restoration of redox balance in microglia via modulating TLR-2/GR interaction. The combination treatment could play a major role in the neuroendocrine-immune regulation of S. aureus induced microglial activation.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Staphylococcus aureus , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Ciprofloxacina/metabolismo , Ciprofloxacina/farmacologia , Peróxido de Hidrogênio/metabolismo , Staphylococcus aureus Resistente à Meticilina/metabolismo , Microglia , Estresse Oxidativo , Receptores de Glucocorticoides/metabolismo
8.
Cell Immunol ; 370: 104441, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34628221

RESUMO

Septic arthritis is a destructive joint disease caused by Staphylococcus aureus. Synovial inflammation involved Th17 proliferation and down regulation of Treg population, thus resolution of inflammation targeting IL-17 may be important to control arthritis. Endogenous inhibition of IL-17 to regulate arthritic inflammation correlating with Th17/Treg cells TLR2 and TNFRs are not done. The role of SOD, CAT and GRx in relation to ROS production during arthritis along with expression of TLR2, TNFR1/TNFR2 in Th17/Treg cells of mice treated with IL-17A Ab/ IL-2 were studied. Increased ROS, reduced antioxidant enzyme activity was found in Th17 cells of SA infected mice whereas Treg cells of IL-17A Ab/ IL-2 treated group showed opposite effects. Neutralization of IL-17 after arthritis cause decreased TNFR1 and increased TNFR2 expression in Treg cells. Thus, neutralization of IL-17 or IL-2 treatment regulates septic arthritis by enhancing anti-inflammatory properties of Treg via antioxidant balance and modulating TLR2/TNFR response.


Assuntos
Artrite Infecciosa/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-2/farmacologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Antioxidantes/metabolismo , Artrite Experimental/imunologia , Interleucina-17/imunologia , Masculino , Camundongos , Espécies Reativas de Oxigênio/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Receptor 2 Toll-Like/imunologia
9.
Immunol Res ; 69(4): 334-351, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34235623

RESUMO

The Gram-negative bacterial lipopolysaccharide (LPS)-induced sepsis has emerged as major concern worldwide due to the pressing need to develop its effective treatment strategies which is not available yet. LPS is the major causative agent in the pathogenesis of septic shock. In macrophages, LPS interacts with cell surface TLR4 leading to reactive oxygen species (ROS), TNF-α, IL-1ß production, oxidative stress and markedly activated the MAPKs and NF-kB pathway. Post cell isolation, the macrophages were subjected to administration with neutralizing antibodies to TLR4 and TNFR1 either alone or in combination prior to LPS challenge. Subsequently, we performed flow cytometric analysis along with Western blots, reactive oxygen species production, and TNF-α, IL-1ß release. Outcomes suggested that the dual blockade of TLR4 and TNFR1 was indeed beneficial in shifting the LPS-induced M1 polarization towards M2. Both TLR4 and TNFR1 exhibited dependency during LPS stimulation. Furthermore, the switch towards the M2 phenotype might be responsible for the decreased levels of TNF-α, IL-1ß, NO, and superoxide anion and the simultaneous elevation in the activity level of anti-oxidant enzymes like SOD, CAT (catalase), and GSH content in the isolated peritoneal macrophages. Simultaneous blocking of both TLR4 and TNFR1 also showed reduced expression of NF-kB, JNK, and COX-2 by promoting TNFR2-mediated TNF-α signaling. The increased arginase activity further confirmed the polarization towards M2. Thus it may be inferred that dual blockade of TLR4 and TNFR1 might be an alternative therapeutic approach for regulating of sepsis in future.


Assuntos
Anticorpos Neutralizantes/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Receptores Imunológicos/antagonistas & inibidores , Animais , Arginase/metabolismo , Radicais Livres/metabolismo , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Oxirredutases/metabolismo , Fenótipo , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Int Immunopharmacol ; 97: 107695, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33962227

RESUMO

Staphylococcus aureus induced brain abscess is a critical health concern throughout the developing world. The conventional surgical intervention could not regulate the abscess-induced brain inflammation. Thus further study over the alternative therapeutic strategy for treating a brain abscess is of high priority. The resident glial cells recognize the invading S. aureus by their cell surface Toll-like receptor-2 (TLR-2). Glucocorticoid receptor (GR) was known for its immunosuppressive effects. In this study, an attempt had been taken to utilize the functional relationship or cross-talking between TLR-2 and GR during the pathogenesis of brain abscesses. Here, the combination of an antibiotic (i.e. ciprofloxacin) and dexamethasone was used to regulate the brain inflammation either in TLR-2 or GR blocking condition. We were also interested to figure out the possible impact of alternative therapy on behavioral impairments. The results indicated that combination treatment during TLR-2 blockade significantly reduced the bacterial burden and abscess area score in the infected brain. However, marked improvements were observed in anxiety, depression-like behavior, and motor co-ordination. The combination treatment after TLR-2 blocking effectively scavenged free radicals (H2O2, superoxide anion, and NO) through modulating antioxidant enzyme activities that ultimately control S. aureus induced glial reactivity possibly via up-regulating GR expression. The exogenous dexamethasone might regulate the GR expression in the brain by increasing the corticosterone concentration and the GC-GR mediated signaling. Therefore, this in-vivo study demonstrates the possible regulatory mechanism of bacterial brain abscess that involved TLR-2 and GR as a part of neuroendocrine-immune interaction.


Assuntos
Abscesso Encefálico/tratamento farmacológico , Ciprofloxacina/farmacologia , Dexametasona/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Abscesso Encefálico/complicações , Abscesso Encefálico/imunologia , Abscesso Encefálico/microbiologia , Ciprofloxacina/uso terapêutico , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Masculino , Camundongos , Doenças Neuroinflamatórias/diagnóstico , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/microbiologia , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/imunologia , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/imunologia , Receptor 2 Toll-Like/metabolismo
11.
Microb Pathog ; 145: 104227, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32360190

RESUMO

Microglial inflammation is the hallmark of S. aureus induced brain abscesses. Conventional antibiotic therapy could not regulate inflammation and the use of steroids in CNS infection remained controversial. To address this issue the effect of dexamethasone along with ciprofloxacin on microglial inflammation has been attempted both in glucocorticoid receptor (GR) opened and blocked condition. We have investigated the effects of ciprofloxacin (0.24 µg/ml, pre-treatment) and dexamethasone (150 nM, pre-treatment) in combination with murine microglia infected with S. aureus for 30, 60 and 90 min by either keeping GR opened or blocked with GR antagonist RU486. Alterations in cellular motility, intracellular killing assay, free radical production, antioxidant enzyme activities, corticosterone, and cytokine levels were determined. The expressions of TLR-2, GR, and other inflammatory markers were determined in terms of this combinatorial treatment. Combination treatment significantly (p < 0.05) reduced the bacterial burden of microglia only when GR remained open and effectively suppressed S. aureus induced oxidative stress by augmenting SOD and catalase enzyme activity and suppressing other pro-inflammatory markers at 90 min. Arginase activity, a critical determinant of microglial polarization was found to be higher after treatment at 60 and 90 min. This situation was reversed when this combination treatment was applied by keeping GR blocked using GR antagonist RU486. Therefore, it can be concluded that combination treatment of ciprofloxacin and dexamethasone could regulate S. aureus induced microglial activation, in the presence of functional GR via utilizing glucocorticoid (GC)-GR pathway and ultimately confers protection to the host from brain inflammation.


Assuntos
Ciprofloxacina , Dexametasona , Glucocorticoides , Microglia , Receptores de Glucocorticoides , Animais , Ciprofloxacina/farmacologia , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Inflamação , Camundongos , Microglia/efeitos dos fármacos , Microglia/microbiologia , Staphylococcus aureus
12.
J Neuroimmunol ; 344: 577262, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450430

RESUMO

Microglial inflammation plays a pivotal role in the pathogenesis of S. aureus induced brain abscesses. The objective of this study was to regulate microglial activation by the combinatorial treatment of ciprofloxacin either with dexamethasone or celecoxib via targeting M1 and M2 polarization. The antibiotic-immunomodulator combinations were applied either by opening both TLR-2 and GR or neutralizing each of them. Our results confirmed that dexamethasone along with ciprofloxacin attenuated bacterial burden along with ROS production more efficiently than celecoxib combination during TLR-2 neutralization. FACS data indicated microglial M1 to M2 switching that was responsible for the better resolution of microglial inflammation.


Assuntos
Ciprofloxacina/administração & dosagem , Dexametasona/administração & dosagem , Microglia/metabolismo , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus , Receptor 2 Toll-Like/metabolismo , Animais , Antibacterianos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Células Cultivadas , Quimioterapia Combinada , Masculino , Camundongos , Microglia/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Receptor 2 Toll-Like/antagonistas & inibidores
13.
Int Immunopharmacol ; 75: 105806, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401378

RESUMO

Microglial inflammation plays crucial role in the pathogenesis of CNS infections including brain abscesses. Staphylococcus aureus (S. aureus) is considered as one of the major causative agents of brain abscesses. Due to the emergence of multidrug resistant bacteria the available treatment options including conventional antibiotics and steroid therapy become ineffective in terms of inflammation regulation which warrants further investigation to resolve this health issue. Microglial TLR-2 plays important roles in the bacterial recognition as well as induction of inflammation whereas glucocorticoid receptor (GR) triggers anti-inflammatory pathways in presence of glucocorticoids (GCs). The main objective of this study was to figure out the interdependency between TLR-2 and GR in presence of exogenous dexamethasone during microglial inflammation as an alternative therapeutic approach. Experiments were done either in TLR-2 neutralized condition or GR blocked condition in presence of dexamethasone. Free radicals production, arginase, superoxide dismutase (SOD), catalase enzyme activities and corticosterone concentration were measured along with Western blot analysis of TLR-2, GR and other inflammatory molecules. The results suggested that dexamethasone pre-treatment in TLR-2 neutralized condition efficiently reduces the inflammatory consequences of S. aureus induced microglial inflammation through up regulating GR expression. During TLR-2 blocking dexamethasone exerted its potent anti-inflammatory activities via suppressing reactive oxygen species (ROS), NO production and up regulating arginase, SOD and catalase activities at the time point of 90 min. Further in-vivo experiments are needed to conclude that dexamethasone could resolve brain inflammation possibly through microglial phenotypic switching from pro-inflammatory M1 to anti-inflammatory M2.


Assuntos
Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Microglia/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus , Receptor 2 Toll-Like/metabolismo , Animais , Masculino , Camundongos , Microglia/metabolismo
14.
Immunol Res ; 67(2-3): 241-260, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31290001

RESUMO

Our earlier studies proposed a radically new idea suggesting interdependency between TNF-α/TNFR1 and IL-1ß/IL-1R pathways in modulation of Staphylococcus aureus-induced CXCL8/CXCR1 axis. However, the effects of inhibition of cytokine receptor mobilization at intracellular level and surface TNFR1 and IL-1R shedding on S. aureus-induced CXCR1 expression have not been studied so far in peritoneal macrophages. This study aimed to investigate the role of inhibition of receptor mobilization from the intracellular pool (using brefeldin A) and surface receptor shedding (using TAPI-1) on CXCR1 expression during dual receptor (TNFR1 plus IL-1R) neutralization in peritoneal macrophages isolated from wild-type Swiss Albino mice. Release of superoxide anion, nitric oxide, and hydrogen peroxide was measured and cytokine production was done by ELISA. Expression of surface receptors (TNFR1, IL-1R, and CXCR1) and inflammatory mediators was studied by Western blot. It was observed that S. aureus-infected macrophages showed elevated ROS production, secretion of TNF-α, IL-1ß, and CXCL8, along with increased expression of surface receptors (TNFR1, IL-1R, and CXCR1), and inflammatory markers (iNOS and COX-2) compared with control or treated groups (p < 0.05). However, prior treatment of macrophages with BFA or TAPI-1 in the presence of anti-TNFR1 antibody and IRAP during S. aureus infection showed significant reduction of all these parameters (p < 0.05). We can conclude that targeting of TNFR1 and IL-1R (with major focus on surface expression study) either through blockage of intracellular receptor trafficking pathway or via surface receptor shedding diminishes TNFR1/IL-1R interaction and consequently downregulates CXCR1 expression along with inflammatory signalling pathways during bacterial infections.


Assuntos
Interações Hospedeiro-Patógeno , Receptores Tipo I de Interleucina-1/metabolismo , Receptores de Interleucina-8A/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/imunologia , Biomarcadores , Citocinas/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Receptores de Interleucina-8A/genética , Infecções Estafilocócicas/genética
15.
Immunol Lett ; 209: 53-66, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30922783

RESUMO

uPA/tPA-mediated activation of plasminogen/plasmin pathway during S. aureus arthritis facilitates the invasion of phagocytes in the affected joint, induces production of cytokines and triggers inflammatory pathways. PAI-1, an effective inhibitor of both uPA and tPA, attenuates plasmin activity. Hence, the objective of our study was to evaluate the effect of exogenously administered PAI-1 on uPA/tPA-mediated activation of plasminogen/plasmin and its impact on the progression of arthritis. The mice were infected with live S. aureus and treated with PAI-1. Mice were sacrificed at 3, 9 and 15 days post infection and thereafter assessment of parameters related to arthritic destruction was done. PAI-1 administration resulted into decrement in uPA and tPA activities with a concomitant reduction in plasmin and MMP-2. A significant decrement in the joint and paw swelling with lower levels of inflammatory cytokines, RANKL and OPN activities were detected in case of early PAI-1 treatment. This study suggests administration of PAI-1 during S.aureus arthritis reduces the severity of arthritis by ameliorating uPA and plasmin-induced inflammatory responses and subsequent arthritic destruction.


Assuntos
Artrite Infecciosa/metabolismo , Artrite Infecciosa/microbiologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Plasminogênio/metabolismo , Transdução de Sinais , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus , Animais , Carga Bacteriana , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Infecções Estafilocócicas/mortalidade
17.
J Neuroimmunol ; 316: 23-39, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29269130

RESUMO

Microglial activation is the most common phenomenon in S. aureus induced brain abscesses as well as other common neurodegenerative diseases. The main objective of this study is to reduce the microglial inflammation with effective bacterial elimination. Ciprofloxacin and celecoxib were used in combination to regulate S. aureus induced oxidative stress and inflammation in primary murine microglial cells. Our results showed that combination treatment effectively killed viable S. aureus and reduced the inflammatory consequences. It can be concluded that lower production of pro-inflammatory cytokines and higher anti-inflammatory IL-10 level may be responsible for microglial polarization switching from pro-inflammatory M1 to anti-inflammatory M2.


Assuntos
Celecoxib/farmacologia , Ciprofloxacina/farmacologia , Citocinas/efeitos dos fármacos , Microglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Inflamação/imunologia , Masculino , Camundongos , Microglia/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus
18.
Immunol Res ; 66(1): 97-119, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29218573

RESUMO

Severity of S. aureus septic arthritis is correlated to prolonged inflammation by inflammatory cytokines like TNF-α, IL-1ß, and IL-6 even after successful elimination of bacteria. Role of TNF-α via TNFR2 is not well established in this aspect. IFN-γ induces TNF-α release from the macrophages augmenting the inflammatory arthritis. IL-10 modulates the levels of pro-inflammatory cytokines promoting resolution of inflammation. TNF-α-TNFR2 signaling upregulates both of these cytokines. Higher level of MMP-2 induction by inflammatory cytokines during arthritis promotes tissue destruction. Whether dual neutralization of TNFR-2 and MMP-2 regulates the severity of S. aureus arthritis by modulating local and systemic cytokine milieu mainly due to TNFR-2 blocking was an obvious question. Here, we attempted the effects of neutralization of MMP-2 and TNFR2 on S. aureus arthritis and its impact on pro-inflammatory cytokines and some other parameters related to tissue destruction. Reduction in arthritis index was noticed in infected mice treated with both MMP-2 inhibitor and TNFR2 antibody. Lowest levels of inflammatory cytokines, iNOS, RANKL, NF-κb, JNK kinase, ROS, and MPO, and lysozyme activity were observed in combined neutralization group at 9 and 15 dpi, but at 3 dpi, most of the above parameters remained elevated due to TNFR2 neutralization. Diminished IL-10 and IFN-γ levels as a result of TNFR2 neutralization at early and later phase of infection respectively might be responsible for these contrasting effects. Overall, it can be suggested that administration of MMP-2 inhibitor and TNFR2 antibody in combination is protective against the inflammation and tissue destruction associated with S. aureus infection during the arthritic episode.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Artrite Infecciosa/terapia , Articulações/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Infecções Estafilocócicas/terapia , Staphylococcus aureus/fisiologia , Animais , Artrite Infecciosa/imunologia , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Articulações/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Infecções Estafilocócicas/imunologia
19.
Microb Pathog ; 113: 460-471, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29162483

RESUMO

Currently, very few studies are available on the expression of CXCR1 in mouse macrophages having both intact TNFR1 and IL-1R or their deficiency in relation to acute S. aureus infection. Peritoneal macrophages from mice neutralized singly for TNFR1or IL-1R, or for both TNFR1 and IL-1R were infected with S. aureus in vitro and their ability to secrete cytokines and reactive oxygen species (ROS) were determined. It was observed that the release of TNF-α and IL-1ß in response to S. aureus infection was decreased in macrophages when both TNFR1 and IL-1R were neutralized. The amount of H2O2, superoxide anion, nitric oxide release and bacterial CFU were significantly decreased in TNFR1 plus IL-1R blocked macrophages when compared with macrophages having intact receptors at 60 min of S. aureus infection. There was decrement of CXCL8 (IL-8) release and expression of CXCR1 in macrophages during dual receptor (TNFR1 plus IL-1R) blocking prior to stimulation with S. aureus. Expression of CXCR1 on murine peritoneal macrophages was evaluated by immunoblots from lysate at 60 min after S. aureus infection. It was observed that at 60 min after S. aureus infection in murine peritoneal macrophages, the expression of CXCR1 was increased significantly (p < 0.05) in comparison to the control groups. CXCR1 expression was decreased significantly (p < 0.05) in macrophages pre-incubated separately with anti-TNFR1 antibody (10 µg/ml) or IL-1R antagonist protein (240 ng/ml) at 60 min after S. aureus infection. However, blocking of both TNFR1 as well as IL-1R in macrophages downregulated the CXCR1expression in comparison to the groups either pre-incubated with anti-TNFR1 antibody or IRAP alone.


Assuntos
Macrófagos Peritoneais/imunologia , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-8A/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/patogenicidade , Animais , Anticorpos Bloqueadores , Contagem de Colônia Microbiana , Citocinas/metabolismo , Regulação da Expressão Gênica , Peróxido de Hidrogênio/metabolismo , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Microb Pathog ; 109: 131-150, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28552636

RESUMO

Literature reveals that interaction with live Staphylococcus aureus (S. aureus) or heat killed S. aureus (HKSA) promotes secretion of CXCL-8 or interleukin-8 (IL-8) from leukocytes, however, the expressions of CXCR1 in murine splenic (SPM), peritoneal macrophages (PM) and resident fresh bone marrow cells (FBMC) have not been identified. Currently, very few studies are available on the functional characterization of CXCR1 in mouse macrophage subtypes and its modulation in relation to acute S. aureus infection. SPM, PM and FBMCs were infected with viable S. aureus or stimulated with HKSA in presence and absence of anti-CXCR1 antibody in this study. We reported here that CXCR1 was not constitutively expressed by macrophage subtypes and the receptor was induced only after S. aureus stimulation. The CXCR1 band was found specific as we compared with human polymorphonuclear neutrophils (PMNs) as a positive control (data not shown). Although, we did not show that secreted IL-8 from S. aureus-infected macrophages promotes migration of PMNs. Blocking of cell surface CXCR1 decreases the macrophage's ability to clear staphylococcal infection, attenuates proinflammatory cytokine production and the increased catalase and decreased superoxide dismutase (SOD) enzymes of the bacteria might indicate their role in scavenging macrophage derived hydrogen peroxide (H2O2). The decreased levels of cytokines due to CXCR1 blockade before S. aureus infection appear to regulate the killing of bacteria by destroying H2O2 and nitric oxide (NO). Moreover, functional importance of macrophage subpopulation heterogeneity might be important in designing new effective approaches to limit S. aureus infection induced inflammation and cytotoxicity.


Assuntos
Células da Medula Óssea/imunologia , Macrófagos Peritoneais/imunologia , Receptores de Interleucina-8/metabolismo , Baço/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Células da Medula Óssea/microbiologia , Catalase/metabolismo , Citocinas/metabolismo , Temperatura Alta , Humanos , Peróxido de Hidrogênio/metabolismo , Inflamação , Interleucina-8/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos Peritoneais/microbiologia , Camundongos , Neutrófilos/imunologia , Óxido Nítrico/metabolismo , Receptores de Interleucina-8/imunologia , Baço/microbiologia , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo
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