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1.
Proc Natl Acad Sci U S A ; 118(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33443169

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that microRNA-132 is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium. miRNA-132 thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of miR-132 in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of miR-132 than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.

2.
Eur J Pain ; 25(1): 189-198, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32965065

RESUMO

BACKGROUND: Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice. METHODS: Male mice C57Bl/6 wild type (WT) and knockouts for bradykinin receptors, B1 (B1-/- ) and B2 (B2-/- ), were used. Mechanical and cold allodynia were evaluated by using von Frey filaments and acetone test, respectively. P-APS was induced by administration of PCX 4 mg/kg, i.v.. ACE inhibitors (captopril and enalapril), antagonists for angiotensin II type 1 (losartan) and type 2 ([AT2R]; PD123319 and EMA 401) receptors were administrated prior the treatment with PCX. RT-PCR was used to analyse the expression of mRNA for B1, B2 and AT2R receptors. RESULTS: Administration of PCX in B1-/- and B2-/- mice induced lower mechanical and cold allodynia compared to the WT. However, the pre-treatment with ACE inhibitors reduced the development of mechanical and cold allodynia in P-APS. Surprisingly, we found that mice pre-treatment with the PD123319 or EMA401, but not losartan, prevented the development of mechanical and cold allodynia induced by PCX. CONCLUSION: Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice, and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans. SIGNIFICANCE: Kinin-kallikrein and renin-angiotensin systems, through B1, B2 and AT2 receptors, potentiates paclitaxel-associated acute pain syndrome (P-APS) in mice. Antagonists for AT2R are potential alternatives to prevent P-APS.

3.
J Exp Med ; 218(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33231615

RESUMO

Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1ß, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.


Assuntos
/patologia , Inflamassomos/metabolismo , Índice de Gravidade de Doença , Apoptose , Comorbidade , Citocinas/biossíntese , Humanos , Pulmão/patologia , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mudanças Depois da Morte , Resultado do Tratamento
4.
bioRxiv ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33200130

RESUMO

Neutrophils overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral neuraminidase inhibitors constrain host neuraminidase activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils. In vivo , treatment with Oseltamivir results in infection control and host survival in murine models of sepsis. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors are host-directed interventions to dampen neutrophil dysfunction in severe infections.

5.
Cell Commun Signal ; 18(1): 141, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894139

RESUMO

BACKGROUND: Low molecular weight carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as inflammatory stimulus in preclinical studies. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the molecular basis involved in Cg-induced macrophages activation and cytokines production. METHODS: Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell lysate were used for ELISA, western blotting, immunofluorescence. Cg-induced mouse colitis was also developed. RESULTS: Here we show that Cg activates peritoneal macrophages to produce pro-inflammatory cytokines such as TNF and IL-1ß. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1ß relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1ß into IL-1ß is dependent on canonical NLRP3 inflammasome activation via Pannexin-1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome components. CONCLUSIONS: In conclusion, we unravel a critical role of the NLRP3 inflammasome in Cg-induced pro-inflammatory cytokines production and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies. Video abstract Carrageenan (Cg) is one the most used flogistic stimulus in preclinical studies. Nevertheless, the molecular basis of Cg-induced inflammation is not totally elucidated. Herein, Lopes et al. unraveled the molecular basis for Cg-induced macrophages production of biological active IL-1ß. The Cg-stimulated macrophages produces pro-IL-1ß depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1ß is dependent on the canonical NLRP3 inflammasome.

6.
Inflamm Res ; 69(12): 1271-1282, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32886146

RESUMO

OBJECTIVE: To investigate the role of IL-33 in gouty arthritis. MATERIAL: 174 Balb/c (wild-type) and 54 ST2-/- mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels. METHODS: Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM. RESULTS: Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1ß and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1ß and TNF-α, and BMDMs from ST2-/- showed reduced levels of these cytokines after stimulus with MSU crystals. CONCLUSION: IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.


Assuntos
Artrite Gotosa/patologia , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-33/farmacologia , Macrófagos/metabolismo , Dor/induzido quimicamente , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Feminino , Humanos , Inflamação/psicologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pessoa de Meia-Idade , Infiltração de Neutrófilos/efeitos dos fármacos , Dor/psicologia , Peroxidase/metabolismo , Superóxidos/metabolismo , Membrana Sinovial/patologia , Ácido Úrico
7.
Artigo em Inglês | MEDLINE | ID: mdl-32979233

RESUMO

Dipyrone (DIP), also known as metamizole, is an over-the-counter analgesic used in Europe and Latin America. Evidence suggesting that inflammatory pain attenuation by DIP is associated with a direct impact on peripheral primary nociceptive neurons through the stimulation of nitric oxide signaling pathway. However, the molecular mechanism by which DIP activates this pathway remains unknown. The PI3Kγ/AKT signaling cascade activation is one of the well-known molecular mechanisms that promote nitric oxide production in sensory neurons. Herein, we investigated the role of the PI3Kγ/AKT signaling cascade in the context of peripheral analgesic effect of DIP. DIP was administered into PGE2 pre-sensitized paws of rats and mechanical hyperalgesia was determined using electronic von Frey test after 1 h. Nonselective or selective pharmacological inhibitors of PI3Kγ and AKT were also administered in DIP-treated rats under paws sensitized with PGE2. Intraplantar injection of DIP attenuated PGE2-induced hyperalgesia in a dose-dependent manner. Treatment with nonselective (wortmannin or LY294002) or selective (AS605240) pharmacological inhibitors of PI3Kγ reduced the peripheral antihypernociceptive effect of DIP. Consistently, AKT selective inhibitor also reversed analgesic DIP effects. Corroborating these data, we found that DIP induced AKT phosphorylation in cultured dorsal root ganglion neurons, which was prevented in the presence of PI3Kγ selective inhibitor. Taken together, these findings provide evidence that peripheral analgesic effect of DIP is dependent on the activation of PI3Kγ/AKT signaling pathway.

8.
J Leukoc Biol ; 108(4): 1215-1223, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32745297

RESUMO

Macrophages are highly plastic cells, responding to diverse environmental stimuli to acquire different functional phenotypes. Signaling through MAPKs has been reported to regulate the differentiation of macrophages, but the role of ERK5 in IL-4-mediated M2 macrophage differentiation is still unclear. Here, we showed that the ERK5 signaling pathway plays a critical role in IL-4-induced M2 macrophage differentiation. Pharmacologic inhibition of MEK5, an upstream activator of ERK5, markedly reduced the expression of classical M2 markers, such as Arg-1, Ym-1, and Fizz-1, as well as the production of M2-related chemokines and cytokines, CCL22, CCL17, and IGF-1 in IL-4-stimulated macrophages. Moreover, pharmacologic inhibition of ERK5 also decreased the expression of several M2 markers induced by IL-4. In accordance, myeloid cell-specific Erk5 depletion (Erk5∆mye ), using LysMcre /Erk5f/f mice, confirmed the involvement of ERK5 in IL-4-induced M2 polarization. Mechanistically, the inhibition of ERK5 did not affect STAT3 or STAT6 phosphorylation, suggesting that ERK5 signaling regulates M2 differentiation in a STAT3 and STAT6-independent manner. However, genetic deficiency or pharmacologic inhibition of the MEK5/ERK5 pathway reduced the expression of c-Myc in IL-4-activated macrophages, which is a critical transcription factor involved in M2 differentiation. Our study thus suggests that the MEK5/ERK5 signaling pathway is crucial in IL-4-induced M2 macrophage differentiation through the induction of c-Myc expression.

9.
Pain ; 161(8): 1730-1743, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32701834

RESUMO

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.

10.
Pain ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32229764

RESUMO

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.

11.
Brain Behav Immun ; 88: 353-362, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32243898

RESUMO

Herpetic neuralgia is a painful condition following herpes zoster disease, which results from Varicella-zoster virus reactivation in the dorsal or trigeminal sensory ganglia. Nevertheless, the pathophysiological mechanisms involved in herpetic neuralgia are not well understood. Recently, we identified, that neuroimmune-glia interactions in the sensory ganglion is a critical mechanism for the development of herpetic neuralgia. Here, we investigate the contribution of S100A9, a well-known pro-inflammatory molecule produced by myeloid cells, for the development of herpetic neuralgia using a murine model of HSV-1 infection. We found that cutaneous HSV-1 infection results in an increase of S100A9 expression in the Dorsal Root Ganglia (DRGs). Infiltrating neutrophils into the DRGs were the main source of S100A9 post HSV-1 infection. Functionally, genetic or pharmacological inhibition of S100A9 impairs the development of HSV-1 infection-induced mechanical pain hypersensitivity. Finally, we found that the pronociceptive role of S100A9 in herpetic neuralgia depends on the TLR4/TNF pathway. These results unraveled previously unknown mechanisms involved in the pathophysiology of herpetic neuralgia and indicate that S100A9 might be an important target for novel therapies aiming acute herpetic neuralgia.

12.
Biochem Pharmacol ; 176: 113862, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32081790

RESUMO

Pain is a classical sign of inflammation, and sensitization of primary sensory neurons (PSN) is the most important mediating mechanism. This mechanism involves direct action of inflammatory mediators such as prostaglandins and sympathetic amines. Pharmacologic control of inflammatory pain is based on two principal strategies: (i) non-steroidal anti-inflammatory drugs targeting inhibition of prostaglandin production by cyclooxygenases and preventing nociceptor sensitization in humans and animals; (ii) opioids and dipyrone that directly block nociceptor sensitization via activation of the NO signaling pathway. This review summarizes basic concepts of inflammatory pain that are necessary to understand the mechanisms of peripheral NO signaling that promote peripheral analgesia; we also discuss therapeutic perspectives based on the modulation of the NO pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dipirona/farmacologia , Inflamação/prevenção & controle , Óxido Nítrico/metabolismo , Dor/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Inflamação/complicações , Inflamação/metabolismo , Dor/etiologia , Dor/metabolismo , Prostaglandinas/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
13.
Inflamm Res ; 69(3): 279-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006078

RESUMO

OBJECTIVE: To compare the unilateral signs of knee osteoarthritis (KOA) 30 and 60 days after anterior cruciate ligament transection (ACLT). Pain, gait function, synovial fluid inflammation, and histopathological changes in the synovial membrane were analyzed, as well as the interaction between the variables. MATERIALS AND METHODS: Male Wistar rats (n = 32; 219.2 ± 18.6 g) were randomly distributed into four groups of eight animals each. Two groups were submitted to unilateral ACLT surgery to induce KOA and analyzed after 30 (KOA30) and 60 days (KOA60). Two control groups (without surgery) were also assessed after the same time periods (C30 and C60). All the groups were evaluated before ACLT from the least to most stressful tests (skin temperature, mechanical response threshold, gait test, thermal response threshold, and joint swelling), as well as 30 and 60 days after surgery. After euthanasia, the synovial fluid and synovial membrane were collected. RESULTS: Thirty days after ACLT, KOA30 showed decrease paw print area and mechanical response threshold, higher joint swelling, skin temperature, leukocyte count, cytokine levels, and synovitis score. No differences were found between KOA30 and KOA60. CONCLUSION: Our data showed that 30 days after ACLT is sufficient to induce signs of KOA in rats, such as pain, functional impairment, and synovial inflammation, suggesting that a shorter time period can be used as an experimental model.


Assuntos
Ligamento Cruzado Anterior/cirurgia , Inflamação/metabolismo , Osteoartrite do Joelho/fisiopatologia , Animais , Movimento Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Articulação do Joelho/patologia , Leucócitos/citologia , Masculino , Osteoartrite do Joelho/etiologia , Medição da Dor , Ratos , Ratos Wistar , Temperatura Cutânea , Líquido Sinovial/química , Líquido Sinovial/citologia , Membrana Sinovial/patologia
14.
J Infect Dis ; 221(9): 1542-1553, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-31783409

RESUMO

BACKGROUND: Liver X receptors (LXRs) are nuclear receptors activated by oxidized lipids and were previously implicated in several metabolic development and inflammatory disorders. Although neutrophils express both LXR-α and LXR-ß, the consequences of their activation, particularly during sepsis, remain unknown. METHODS: We used the model of cecal ligation and puncture (CLP) to investigate the role of LXR activation during sepsis. RESULTS: In this study, we verified that LXR activation reduces neutrophil chemotactic and killing abilities in vitro. Mice treated with LXR agonists showed higher sepsis-induced mortality, which could be associated with reduced neutrophil infiltration at the infectious foci, increased bacteremia, systemic inflammatory response, and multiorgan failure. In contrast, septic mice treated with LXR antagonist showed increased number of neutrophils in the peritoneal cavity, reduced bacterial load, and multiorgan dysfunction. More important, neutrophils from septic patients showed increased ABCA1 messenger ribonucleic acid levels (a marker of LXR activation) and impaired chemotactic response toward CXCL8 compared with cells from healthy individuals. CONCLUSIONS: Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.

16.
J Ethnopharmacol ; 252: 112496, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31870795

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis is a natural product produced by honeybees used as a medicine at least to 300 BC. In the last decades, several studies showed biological and pharmacological properties of propolis, witch scientifically explains the empirical use for centuries. The anti-inflammatory activity of propolis with the purpose to reduce Th2 inflammation has been evaluated in allergic asthma. However, it remains to be determined how propolis negatively regulates the immune response after allergen re-exposure. AIM OF THE STUDY: We hypothesized that the anti-inflammatory activity of propolis is dependent on the induction of myeloid derived suppressor cells (MDSC) and regulatory T cells. MATERIALS AND METHODS: To assess this hypothesis, we used an ovalbumin-induced asthma model to evaluate the effect of EPP-AF® dry extract from Brazilian green propolis. RESULTS: Propolis treatment decreased pulmonary inflammation and mucus production as well as eosinophils and IL-5 in the broncoalveolar lavage. Propolis enhanced also in vitro differentiation and in vivo frequency of lung MDSC and CD4+Foxp3+ regulatory T cells. CONCLUSIONS: Together these results confirm the immunomodulatory potential of propolis during sensitization and challenge with allergen. In addition, the collecting findings show, for the first time, that propolis increases the frequency of MDSC and CD4+Foxp3+ regulatory T cells in the lungs, and suggest that it could be use as target for development of new immunotherapy or adjuvant immunotherapy for asthma.


Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Células Supressoras Mieloides/efeitos dos fármacos , Própole/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Alérgenos , Animais , Anti-Inflamatórios/farmacologia , Asma/induzido quimicamente , Asma/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Fatores Imunológicos/farmacologia , Imunoterapia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-5/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Ovalbumina , Própole/farmacologia , Linfócitos T Reguladores/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
17.
Eur J Pharmacol ; 863: 172706, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31568782

RESUMO

It is well established that sepsis induces vascular hyporesponsiveness to vasoconstrictors. Perivascular adipose tissue (PVAT) displays anti-contractile action in various blood vessels. We hypothesized that sepsis would increase the anti-contractile effect of PVAT aggravating sepsis-induced vasoplegia. Male Wistar Hannover rats were subjected to lethal sepsis by cecal ligation and puncture (CLP) method. Aorta or PVAT were collected for functional or biochemical assays 6 h after CLP surgery. Functional experiments showed that sepsis increased the anti-contractile action of PVAT in both endothelium-intact and endothelium-denuded aortas. Carboxy-PTIO, L-NAME and ODQ reversed the hypocontractility mediated by PVAT in aortas from septic rats. Inhibition of nNOS and iNOS with 7-nitroindazole and 1400 W attenuated PVAT-mediated hypocontractility during sepsis. Similar results were found in the presence of indomethacin and Ro1138452, a selective prostacyclin IP receptor antagonist. However, neither tiron nor catalase affected phenylephrine-induced contraction in aortas from septic rats. Increased levels of superoxide anion (O2•-) and 6-keto-prostaglandin F1α (stable product of prostacyclin) were detected in PVAT from septic rats. In situ quantification of reactive oxygen species and nitric oxide (NO) using fluorescent dyes revealed increased levels of both in PVAT from septic rats. The novelty of our study is that PVAT contributes to sepsis-induced vasoplegia by releasing NO and prostacyclin. These findings suggested that signaling pathways in PVAT may be considered as potential novel pharmacological therapeutic targets during sepsis-induced vasoplegia.


Assuntos
Tecido Adiposo/patologia , Sepse/complicações , Vasoplegia/etiologia , Vasoplegia/patologia , 6-Cetoprostaglandina F1 alfa/metabolismo , Tecido Adiposo/metabolismo , Animais , Aorta/patologia , Dinoprostona/metabolismo , Masculino , Óxido Nítrico/biossíntese , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Vasoplegia/metabolismo
18.
PLoS Pathog ; 15(9): e1007934, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31479495

RESUMO

Mayaro virus (MAYV) is an arbovirus that circulates in Latin America and is emerging as a potential threat to public health. Infected individuals develop Mayaro fever, a severe inflammatory disease characterized by high fever, rash, arthralgia, myalgia and headache. The disease is often associated with a prolonged arthralgia mediated by a chronic inflammation that can last months. Although the immune response against other arboviruses, such as chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), has been extensively studied, little is known about the pathogenesis of MAYV infection. In this study, we established models of MAYV infection in macrophages and in mice and found that MAYV can replicate in bone marrow-derived macrophages and robustly induce expression of inflammasome proteins, such as NLRP3, ASC, AIM2, and Caspase-1 (CASP1). Infection performed in macrophages derived from Nlrp3-/-, Aim2-/-, Asc-/-and Casp1/11-/-mice indicate that the NLRP3, but not AIM2 inflammasome is essential for production of inflammatory cytokines, such as IL-1ß. We also determined that MAYV triggers NLRP3 inflammasome activation by inducing reactive oxygen species (ROS) and potassium efflux. In vivo infections performed in inflammasome-deficient mice indicate that NLRP3 is involved with footpad swelling, inflammation and pain, establishing a role of the NLRP3 inflammasome in the MAYV pathogenesis. Accordingly, we detected higher levels of caspase1-p20, IL-1ß and IL-18 in the serum of MAYV-infected patients as compared to healthy individuals, supporting the participation of the NLRP3-inflammasome during MAYV infection in humans.


Assuntos
Infecções por Alphavirus/imunologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adulto , Idoso , Infecções por Alphavirus/metabolismo , Animais , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Vírus Chikungunya/metabolismo , Vírus da Dengue/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos/imunologia , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espécies Reativas de Oxigênio/metabolismo , Togaviridae/patogenicidade , Zika virus/metabolismo
19.
Biomolecules ; 9(8)2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31431000

RESUMO

Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1-/-) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1-/- exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1-/- and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1-/- mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1-/- mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1-/- mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation.


Assuntos
Metaloendopeptidases/metabolismo , Animais , Comportamento Animal , Feminino , Masculino , Metaloendopeptidases/deficiência , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo
20.
Sci Rep ; 9(1): 8379, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182740

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. Individuals with RA have a higher risk of periodontitis and periodontitis has been linked to RA through the production of enzymes by periodontal pathogens that citrullinate proteins. This linkage is supported by findings that periodontitis is associated with increased RA severity and treatment of periodontitis can improve the symptoms of RA. The possible mechanism for this association is through dysbiosis of the oral microbiota triggered by RA-induced systemic inflammation. We examined the RA status of subjects by measuring the number of tender and swollen joints, anti-citrullinated protein antibody and rheumatoid factor. Periodontal disease status and salivary cytokine levels were measured, and dental plaque analyzed by 16S rRNA high throughput sequencing. RA patients had a higher bacterial load, a more diverse microbiota, an increase in bacterial species associated with periodontal disease, more clinical attachment loss, and increased production of inflammatory mediators including IL-17, IL-2, TNF, and IFN-γ. Furthermore, changes in the oral microbiota were linked to worse RA conditions. Our study provides new insights into the bi-directional relationship between periodontitis and RA and suggest that monitoring the periodontal health of RA patients is particularly important.


Assuntos
Artrite Reumatoide/genética , Disbiose/genética , Periodontite/genética , Adulto , Anticorpos Anti-Proteína Citrulinada/genética , Artrite Reumatoide/complicações , Artrite Reumatoide/microbiologia , Artrite Reumatoide/patologia , Citocinas/genética , Disbiose/complicações , Disbiose/microbiologia , Disbiose/patologia , Feminino , Humanos , Interleucina-17/genética , Masculino , Microbiota/genética , Pessoa de Meia-Idade , Boca/microbiologia , Boca/patologia , Periodontite/complicações , Periodontite/microbiologia , Periodontite/patologia , Periodonto/microbiologia , Periodonto/patologia , RNA Ribossômico 16S/genética
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