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Item does not contain fulltext The mechanisms underlying innate immune memory have been extensively explored in the last decades but are in fact largely unknown. Although the specificity of adaptive immune memory in vertebrates is ensured through the recombination of immunoglobulin family genes and clonal expansion, the basic mechanisms of innate immune cells' nonspecific increased responsiveness rely on epigenetic, transcriptional, and metabolic programs after transient stimulation. Changes in these programs result in enhanced responsiveness to secondary challenges with a wide variety of stimuli. This phenomenon is termed "trained immunity" or "innate immune memory." On one hand, trained immunity improves the response to infections and vaccination, facilitating stronger innate immune responses and enhanced protection against a variety of microbial stimuli. Conversely, trained immunity may contribute to the pathophysiology of cardiovascular, autoinflammatory, and neurodegenerative diseases. In this review, we gather the current body of knowledge in this field and summarize the foundations and mechanisms of trained immunity, the different cell types involved, its consequences for health and disease, and the potential of its modulation as a therapeutic tool.

Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01164-w.

Although studies have shown positive effects of gonadotropin releasing hormone (GnRH) or prostaglandin F2α (PGF2α) at the moment of fixed-time artificial insemination (FTAI) in the conception rate (CR) of cattle, its effects on treatments based on progesterone (P4) and estradiol benzoate (EB) is still not conclusive. The objective of this study was (1) to evaluate the effect of a PGF2α analogue at FTAI in the CR of crossbred beef cows submitted to a 11d FTAI protocol based on P4 and EB; and (2) to describe the CR between PGF2α-treated and control cows in different body condition scores (BCS) and parity categories. Crossbred (½ Nellore and ½ Angus) beef cows were submitted to a synchronization protocol and randomly assigned into 2 groups: Control (n = 163), at FTAI cows received 2 mL of saline solution as a placebo, and PGF2α (n = 163), at FTAI cows were treated with PGF2α analogue (10 mg of dinoprost tromethamine). Pregnancy diagnosis was performed 33d post-FTAI. Binary logistic regression model was used to analyze the effect of PGF2α treatment on CR. There was no difference in CR between PGF2α and control groups (P > 0.05; odds ratio (OR) = 0.92; confidence interval (CI) = 0.59-1.4). A greater CR was found in heifers (P = 0.0006, OR = 2.65, CI = 1.61 - 4.38) and multiparous (P = 0.0006, OR = 2.12, CI = 1.04 - 4.3) when compared to primiparous cows. Cows with low BCS (4; 9-point scale) showed lower CR when compared with moderate BCS (5-6; 9-point scale) (P < 0.05; OR = 0.10; CI = 0.06 - 0.18). There was no numerical difference on CR between PGF2α-treated and control cows in different BCS and parity categories. The results suggested that the CR in this study was not influenced by 10 mg PGF2α analogue at FTAI.

Background Visual search abilities are essential to everyday life activities and are known to be affected in Alzheimer's disease (AD). However, little is known about visual search efficiency in mild cognitive impairment (MCI), a transitive state between normal aging and dementia. Eye movement studies and machine learning methods have been recently used to detect oculomotor impairments in individuals with dementia. Objective The aim of the present study is to investigate the association between eye movement metrics and visual search impairment in MCI and AD. Methods 127 participants were tested: 43 healthy controls, 51 with MCI, and 33 with AD. They completed an eyetracking visual search task where they had to find a previously seen target stimulus among distractors. Results Both patient groups made more fixations on the screen when searching for a target, with longer duration than controls. MCI and AD fixated the distractors more often and for a longer period of time than the target. Healthy controls were quicker and made less fixations when scanning the stimuli for the first time. Machine-learning methods were able to distinguish between controls and AD subjects and to identify MCI subjects with a similar oculomotor profile to AD with a good accuracy. Conclusion Results showed that eye movement metrics are useful for identifying visual search impairments in MCI and AD, with possible implications in the early identification of individuals with high-risk of developing AD.

Although studies have shown positive effects of gonadotropin releasing hormone (GnRH) or prostaglandin F

Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix, with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) of Sporothrix spp. is a pathogen associated molecular pattern (PAMP). Interestingly, S. brasiliensis PRM has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the host’s immune response and may explain the severity of sporotrichosis caused by S. brasiliensis. Here we demonstrate that S. brasiliensis yeasts and its PRM (S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-α, IL-6 and IL-1β and induction of T-helper cytokines IFN-γ, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1β and IL-1α production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1β independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis. The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.

Cryopreservation and transplantation of ovarian tissue are proposed methods for the restoration of endocrine function and reproductive potential. Therefore, this study aimed to evaluate the effects of vitrification and xenotransplantation on follicle viability, activation, stromal cell integrity, vascularization, and micronuclei formation. Bovine fetal ovaries were fragmented and assigned to the following groups: Fresh control (FC), ovarian fragments immediately fixed; Vitrified control (VC), ovarian fragments vitrified; Vitrified xenotransplanted (VX), ovarian fragments vitrified and xenotransplanted; and Fresh xenotransplanted (FX), ovarian fragments xenotransplanted. Ovarian fragments were grafted in female BALB/c mice and recovered after 14 days. Follicular viability was preserved (P 0.05) in VC group. The rate of developing follicles was greater (P 0.05) in the FX group compared to other groups. Follicular density was higher (P 0.05) in the VC group than the FC, VX, and FX groups. A decrease (P 0.05) of stromal cell density was recorded after vitrification (VC vs. FX). Blood vessel density decreased in VC, VX, and FX groups compared with the FC group, and blood vessel density was correlated with follicular viability (positively; P = 0.07) and developing follicles (negatively; P 0.001). Both vitrification and xenotransplantation groups (VC, VX, and FX) had a greater (P 0.05) number of cells with one MN compared to the FC group. In summary, our findings showed that both vitrification and xenotransplantation modified blood vessel, follicular and stromal cell densities, follicular viability and activation, and micronuclei formation in ovarian tissue.

Item does not contain fulltext BACKGROUND: Cells of the innate immune system undergo long-term functional reprogramming in response to Bacillus Calmette-Guérin (BCG) exposure via a process called trained immunity, conferring nonspecific protection to unrelated infections. Here, we investigate whether BCG-induced trained immunity is able to protect against infections caused by different Leishmania spp., protozoa that cause cutaneous and mucosal or visceral lesions. METHODS: We used training models of human monocytes with BCG and subsequent infection by L. braziliensis, L. amazonensis and L. infantum, and the vaccination of wild-type and transgenic mice for IL-32γ before in vivo challenge with parasites. RESULTS: We demonstrated that monocytes trained with BCG presented enhanced ability to kill L. braziliensis, L. amazonensis and L. infantum through increased production of reactive oxygen species. Interleukin (IL)-32 appears to play an essential role in the development of trained immunity. Indeed, BCG exposure induced IL-32 production in human primary monocytes, both mRNA and protein. We have used a human IL-32γ transgenic mouse model (IL-32γTg) to study the effect of BCG vaccination in different Leishmania infection models. BCG vaccination decreased lesion size and parasite load in infections caused by L. braziliensis and reduced the spread of L. amazonensis to other organs in both infected wild-type (WT) and IL-32γTg mice. In addition, BCG reduced the parasite load in the spleen, liver and bone marrow of both WT and IL-32γTg mice infected with L. infantum. BCG vaccination increased inflammatory infiltrate in infected tissues caused by different Leishmania spp. In all infections, the presence of IL-32γ was not mandatory, but it increased the protective and inflammatory effects of BCG-induced training. CONCLUSIONS: BCG's ability to train innate immune cells, providing protection against leishmaniasis, as well as the participation of IL-32γ in this process, pave the way for new treatment strategies for this neglected infectious disease.

Item does not contain fulltext Neglected tropical diseases annually account for several million infections worldwide. Efficacious treatment for these poorly understood infectious diseases is often limited to ineffective, expensive, and toxic therapies such as the SbV used for leishmaniasis patients. Here, we review the latest discoveries and literature on the molecular pathways, cell types, and immune mediators involved in the immune response to infection with New World Leishmania spp. in humans and their interaction with the adaptive and innate immune system. Novel developments in the field of trained innate immunity and the recently described role of IL-32 are emphasized as potential immunotherapeutic treatments for the management of leishmaniasis.

O câncer de mama é o tipo de câncer mais comum em mulheres no Brasil e no mundo. Pacientes com câncer de mama frequentemente apresentam alterada resposta inflamatória após desafios imunes, bem como elevada prevalência de comorbidades psiquiátricas e disfunções cognitivas. Modelos animais de câncer indicam que os tumores por si só são suficientes para exacerbar as respostas neuroinflamatórias após um desafio imunológico. No entanto, tumores primários geralmente não estão presentes em sobreviventes de câncer, e as consequências comportamentais destas respostas alteradas permanecem desconhecidas. Portanto, no presente trabalho, utilizando modelo murino, primeiramente foi estudada se a indução de tumor mamário exacerba respostas inflamatórias (tanto sistêmica quanto em estruturas encefálicas envolvidas com o controle da resposta ao estresse) e a extensão em que a remoção do tumor (mastectomia) influencia estas respostas. Ainda, avaliamos o comportamento doentio após um desafio imunológico com lipopolissacarídeo (LPS). Por fim, investigamos se as alterações neuroimunoendócrinas induzidas por tumores influenciam parâmetros cognitivos, bem como o comportamento do tipo ansioso em repouso. Os tumores diminuíram os níveis de mRNA de Tnf-?, Il-1? e Il-6 em múltiplas regiões encefálicas no grupo tumor após desafio com LPS. Este efeito foi atenuado em camundongos mastectomizados em alguns casos. Os tumores também atenuaram parâmetros do comportamento doentio (temperatura corporal e locomoção) durante o período de 24 horas após a injeção de LPS em comparação com os controles tratados com LPS. Os camundongos mastectomizados exibiram respostas intermediárias. Adicionalmente, foram avaliados parâmetros cognitivos e relacionados à ansiedade em diferentes fases do ciclo claro-escuro, bem como a expressão basal de 88 genes envolvidos na resposta imune inata e adaptativa em estruturas cerebrais por PCR array. Dentre os parâmetros comportamentais, observou-se que os tumores induzem comportamento semelhante à fadiga na fase ativa, o qual persiste mesmo após a remoção tumoral. Os tumores também regularam positivamente a expressão de vários genes relacionados às respostas imune, tais como Il1-?, Il1r1, e Icam1, enquanto a remoçãoxi tumoral reestabeleceu os níveis basais de expressão destes marcadores. Tomados em conjunto, nossos resultados indicam que a experiência tumoral induz alterações duradouras na sinalização neuroimune funcional, as quais podem além de afetar a resposta inflamatória e comportamental a desafios imunes subsequentes, contribuir para a persistência de comorbidades neuropsiquiátricas nos sobreviventes de câncer. Desta forma, concluímos que elucidação dos mecanismos pelos quais o desenvolvimento tumoral altera a sinalização neuroimune e induz comorbidades comportamentais é essencial para refinar as estratégias de tratamento e garantir qualidade de vida para a crescente população de sobreviventes de câncer. Breast cancer is the most common type of cancer among women in Brazil and worldwide. Breast cancer patients often present altered inflammatory responses after an immune challenge, as well as increased prevalence of psychiatric comorbidities and cognitive dysfunctions. Animal cancer models suggest that tumors alone are sufficient to exacerbate neuroinflammatory responses following an immune challenge. Since, primary tumors are generally not present in cancer survivors, the behavioral consequences of these altered responses remain unclear. Therefore, in the present study, using a rodent model, we first studied whether mammary tumor induction exacerbates inflammatory responses (both systemic and in brain structures involved in the control of stress response) and the extent to which tumor removal influences these responses. Then, we evaluated the sickness behavior in response to an immune challenge with lipopolysaccharide (LPS). Finally, we investigated whether the tumor-induced neuroimmunoendocrine changes influence cognitive parameters, and anxiety-like behavior at rest. Tumors decreased Tnf-?, Il-1? and Il-6 mRNA levels in multiple brain regions after LPS challenge. This impaired neuroinflammatory response was attenuated in mastectomized mice in some cases. Tumors also attenuated parameters sickness behavior (body temperature and locomotion) during the 24-hour period after LPS injection compared to LPS-treated controls. The mastectomized mice exhibited intermediate responses. The same procedure of tumor induction and removal was performed in another cohort of animals to evaluate cognitive and anxiety-related parameters in different phases of the lightdark cycle, as well as the basal expression of 88 genes involved in the innate and adaptive immune response in the brain structures by PCR array. Tumors induced fatigue during the active phase, which persisted after tumor removal. Tumors also increased the brain expression of various genes of immune responses, such as Il1-?, Il1r1, and Icam1, which were reversed by tumor removal Taken together, our results indicate that tumor experience induces lasting changes in functional neuroimmune signaling, which may affect the inflammatory and behavioral response to subsequent immune challenges and contribute to persistence ofxiii neuropsychiatric comorbidities in cancer survivors. Thus, we conclude that the identification of the mechanisms by which tumor development alters neuroimmune signaling and induces behavioral comorbidities is essential to refine treatment approach and provide quality of life for the growing population of cancer survivors.

Objective: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-β treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients. Methods: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). Results: In patients treated with IFN-β, tumor necrosis factor (TNF)-α production after exposure to TLR2 agonist (Pam3Cys) was lower than in healthy controls and untreated MS patients. However, IFN-β treatment had no significant effect on TNF-α production after TLR4 agonist (LPS) stimulation. On the other hand, interleukin (IL)-10 production was increased in TLR4- but not in TLR2-stimulated whole-blood cell culture from MS patients under IFN-β treatment when compared to the controls. No differences in TNF-α or IL-10 mRNA expression in PBMCs from healthy controls and untreated or treated MS patients were detected, although PBMCs from treated patients presented higher levels of IL-32γ mRNA than those from controls. Conclusions: Our data suggest that IFN-β treatment alters the TLR-dependent immune response of PBMCs from MS patients. This may contribute to the beneficial effects of IFN-β treatment.

Summary Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by β-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory., Graphical Abstract, Highlights • Set7 regulates enhanced cytokine production in trained immunity in vitro • Set7 knockout mice are unable to mount trained immunity against endotoxin challenge • Set7 modulates cellular respiration in β-glucan-trained macrophages • Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells, Using a combination of pharmacological and genetic approaches, Keating et al. show that the Set7 methyltransferase is a regulator of trained immunity induced by β-glucan. Activation of Set7 increases oxidative phosphorylation in trained cells via histone lysine methylation at gene enhancers of key enzymes of the TCA cycle.

Studies in IL‐32 transgenic mice and in vitro suggest that IL‐32 may have protective effects against Mycobacterium tuberculosis, but so far there are barely any studies in humans. We studied the role of IL‐32 and its splice variants in tuberculosis (TB) in vivo and in vitro. Blood transcriptional analysis showed lower total IL‐32 mRNA levels in pulmonary TB patients compared to patients with latent TB infection and healthy controls. Also, among Indonesian household contacts who were heavily exposed to an infectious TB patient, IL‐32 mRNA levels were higher among those who remained uninfected compared to those who became infected with M. tuberculosis. In peripheral blood mononuclear cells from healthy donors, we found that IL‐32γ, the most potent isoform, was down‐regulated upon M. tuberculosis stimulation. This decrease in IL‐32γ was mirrored by an increase of another splice variant, IL‐32β. Also, a higher IL‐32γ/IL‐32β ratio correlated with IFN‐γ production, whereas a lower ratio correlated with production of IL‐1Ra, IL‐6, and IL‐17. These data suggest that IL‐32 contributes to protection against M. tuberculosis infection, and that this effect may depend on the relative abundance of different IL‐32 isoforms., IL‐32 is associated with resistance against M. tuberculosis infection. Mycobacterium tuberculosis induces IL‐32 splicing into different isoforms, which correlates with specific cytokine profiles.

Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and epigenetic reprogramming. Because of its previous associations to metabolic and epigenetic memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesized that the Set7 methyltransferase has an important role in trained immunity induced by the prototypical inducer of trained immunity β-glucan. Using pharmacological studies of human primary monocytes, we identified trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally revealed Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as an important epigenetic regulator of trained immunity, these findings provide mechanistic insight into metabolic changes and underscore the importance of characterizing key regulatory circuits of innate immune memory.

Interleukin 32 (IL-32) is an intracellular cytokine produced by immune and non immune cells after different stimuli. It contributes to inflammation and control of intracellular pathogens mainly by inducing proinflammatory cytokines and microbicidal molecules. Evidence is rising showing that IL-32 can be considered an endogenous danger signal after tissue injury, amplifying the inflammatory process and acquired immune responses. It seems to be a master regulator of intracellular infectious diseases. In this review, first the general properties of IL-32 are described followed by its role in the immunopathogenesis of inflammatory and infectious diseases. Roles of IL-32 in the control of infectious diseases caused by intracellular pathogens are reported, and later a focus on IL-32 in leishmaniases, diseases caused by an intracellular protozoan, is presented.

The role of interleukin (IL-)32 in inflammatory conditions is well-established, however, the mechanism behind its role in atherosclerosis remains unexplained. Our group reported a promoter single nucleotide polymorphism in IL-32 associated with higher high-density lipoprotein (HDL) concentrations. We hypothesize that endogenous IL-32 in liver cells, a human monocytic cell line and carotid plaque tissue, can affect atherosclerosis by regulating (HDL) cholesterol homeostasis via expression of cholesterol transporters/mediators.Human primary liver cells were stimulated with recombinant human (rh)TNFα and poly I:C to study the expression of IL-32 and mediators in cholesterol pathways. Additionally, IL-32 was overexpressed in HepG2 cells and overexpressed and silenced in THP-1 cells to study the direct effect of IL-32 on cholesterol transporters expression and function.Stimulation of human primary liver cells resulted in induction of IL-32α, IL-32β and IL-32γ mRNA expression (p 0.01). A strong correlation between the expression of IL-32γ and ABCA1, ABCG1, LXRα and apoA1 was observed (p 0.01), and intracellular lipid concentrations were reduced in the presence of endogenous IL-32 (p 0.05). Finally, IL32γ and ABCA1 mRNA expression was upregulated in carotid plaque tissue and when IL-32 was silenced in THP-1 cells, mRNA expression of ABCA1 was strongly reduced.Regulation of IL-32 in human primary liver cells, HepG2 and THP-1 cells strongly influences the mRNA expression of ABCA1, ABCG1, LXRα and apoA1 and affects intracellular lipid concentrations in the presence of endogenous IL-32. These data, for the first time, show an important role for IL32 in cholesterol homeostasis.

Cryptococcal species vary in capsule and cell size, thermotolerance, geographic distribution, and affected populations. Cryptococcus gattii sensu stricto and C. deuterogattii affect mainly immunocompetent hosts; however, C. bacillisporus , C. decagattii , and C. tetragattii cause infections mainly in immunocompromised hosts. This study aimed to compare the capacities of different species of the C. gattii species complex to induce cytokines and antimicrobial molecules in human peripheral blood mononuclear cells (PBMCs). Cryptococcus bacillisporus and C. deuterogattii induced the lowest levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 among the five species of the C. gattii complex. Cryptococcus deuterogattii induced higher levels of IL-22 than those induced by C. tetragattii and the environmental species C. flavescens . In addition, C. bacillisporus and C. gattii sensu stricto proliferated inside human monocyte-derived macrophages after 24 h of infection. All Cryptococcus species were able to generate reactive oxygen species (ROS) in human PBMCs, with C. bacillisporus and C. deuterogattii being more efficient than the other species. In conclusion, C. bacillisporus and C. deuterogattii induce lower levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and higher ROS levels than those induced by the other species. Species of the Cryptococcus gattii complex have different abilities to induce cytokine and ROS production by human PBMCs.

Visceral leishmaniasis (VL) is a chronic parasitic disease caused by Leishmania infantum in the Americas. During VL, several proinflammatory cytokines are produced in spleen, liver, and bone marrow. However, the role of interleukin-32 (IL-32) has not been explored in this disease. IL-32 can induce production of proinflammatory cytokines in innate immune cells and polarize the adaptive immune response. Herein, we discovered that L. infantum antigens induced expression of mRNA mainly for the IL-32γ isoform but also induced low levels of the IL-32β transcript in human peripheral blood mononuclear cells. Furthermore, infection of human IL-32γ transgenic mice (IL-32γTg mice) with L. infantum promastigote forms increased IL-32γ expression in the spleen and liver. Interestingly, IL-32γTg mice harbored less parasitism in the spleen and liver than wild-type (WT) mice. In addition, IL-32γTg mice showed increased granuloma formation in the liver compared to WT mice. The protection against VL was associated with increased production of nitric oxide (NO), interferon gamma (IFN-γ), IL-17A, and tumor necrosis factor alpha by splenic cells restimulated ex vivo with L. infantum antigens. In parallel, there was an increase in the number of Th1 and Th17 T cells in the spleens of IL-32γTg mice infected with L. infantum . IL-32γ induction of IFN-γ and IL-17A expression was found to be essential for NO production by splenic cells of infected animals. These data indicate that IL-32γ potentiates the Th1/Th17 immune response during experimental VL, thus contributing to the control of L. infantum infection.

Osteosarcoma is the most prevalent primary bone cancer. Although it has a global impact of approximately 1 to 3 cases/million a year, its etiopathophysiology is still unknown. Moreover, the immune response to its development is very individual as well as variable. Particular emphasis has been placed on the study of the immunoregulatory role of cytokines in osteosarcoma. In this scenario, newly identified cytokine networks have emerged. A deep understanding on the complex interplay of cytokines in osteosarcoma may have prognostic importance. In this review, we seek to highlight the classic roles of cytokines in osteosarcoma, to describe the role of new players in the emerging cytokine networks, and to discuss the therapeutic targets that encompass the complexity and implications of this network.

Snake venom has been the subject of numerous studies in an attempt to find properties and biological effects that may be beneficial to man. In this study we evaluatedin vitrothe effects ofCrotalus durissus terrificus(Cdt) andCrotalus durissus collilineatus(Cdc) venom in human peripheral blood mononuclear cells (PBMCs). At 24 h, a significant decrease of viable cells was observed in cells stimulated with the Cdc venom at 0.0005 mg/mL and 0.005 mg/mL compared to the negative control. At 48 h, a significant decrease of viable cells was observed only in cells stimulated with Cdc venom at 0.005 mg/mL. A significant increase of TNF-αand IL-10 was detected 48 hours after culture of PBMC with Cdc, but not with Cdt venom. The expression of CD69 and PD1 (programmed death-1), activation and regulatory cell markers, on CD8+ and CD8− T cells did not change in the presence of Cdt and Cdc venom. Our results suggest the presence of proinflammatory and anti-inflammatory components in the Cdc venom. Further analysis should be done to identify those Cdc venom components as it has been done for the Cdt venom by other authors, indicating that modulatory components are found in the venom of different species ofCrotalussnakes.

Contains fulltext : 169721.pdf (Publisher’s version ) (Closed access) Interleukin 32 (IL-32) is a proinflammatory cytokine, expressed as 9 distinct isoforms. The most active isoform is the predominantly intracellular-functioning IL-32gamma. Involvement of IL-32 in infectious diseases is increasingly being appreciated. Production of IL-32 promotes pathways that serve to control bacterial infection, especially those caused by mycobacteria. A similar role for this cytokine is observed in the cellular response to viral infections. In addition to its protective effects against microorganisms, IL-32 is involved in immunopathogenesis of some infectious diseases. In parasitic diseases, it has been demonstrated that this cytokine is induced by Leishmania infection. In this review, we summarize the present data on the role of IL-32 in infectious diseases, highlighting this cytokine as new target for control of infections.

Contains fulltext : 177364.pdf (Publisher’s version ) (Open Access) BACKGROUND: Interleukin 32 (IL-32) is a pro-inflammatory cytokine induced in patients with American tegumentary leishmaniasis (ATL) caused by Leishmania braziliensis. Here, we investigated whether IL-32 is also expressed in patient lesions caused by L. amazonensis. In addition, we evaluated experimental L. amazonensis and L. braziliensis infections in C57BL/6 transgenic mice for human IL-32gamma (IL-32gammaTg) in comparison with wild-type (WT) mice that do not express the IL-32 gene. RESULTS: Human cutaneous lesions caused by L. amazonensis express higher levels of IL-32 than healthy control skin. In mice, the presence of IL-32gamma promoted the control of cutaneous lesions caused by L. braziliensis, but not lesions caused by L. amazonensis in an ear dermis infection model. In addition, IL-32gammaTg mice displayed less tissue parasitism and inflammation in IL-32gammaTg than WT mice during the healing phase of L. braziliensis infection. Production of antigen-specific pro-inflammatory cytokines was higher in IL-32gammaTg mice than in WT mice during L. braziliensis infection but not during L. amazonensis infection. CONCLUSIONS: Human cutaneous lesions caused by L. amazonensis express high levels of IL-32. In mice, the presence of IL-32gamma contributes to the lesion healing caused by L. braziliensis but not by L. amazonensis. Data suggest that despite the ability for both species to induce IL-32 in humans, the connections between this cytokine and other immune players induced by related species of parasites can lead to distinct outcomes of the murine infections.

Contains fulltext : 169697.pdf (Publisher’s version ) (Open Access) Patients with rheumatoid arthritis (RA) are at higher risk of developing cardiovascular diseases (CVD). Interleukin (IL)-32 has previously been shown to be involved in the pathogenesis of RA and might be linked to the development of atherosclerosis. However, the exact mechanism linking IL-32 to CVD still needs to be elucidated. The influence of a functional genetic variant of IL-32 on lipid profiles and CVD risk was therefore studied in whole blood from individuals from the NBS cohort and RA patients from 2 independent cohorts. Lipid profiles were matched to the specific IL-32 genotypes. Allelic distribution was similar in all three groups. Interestingly, significantly higher levels of high density lipoprotein cholesterol (HDLc) were observed in individuals from the NBS cohort and RA patients from the Nijmegen cohort homozygous for the C allele (p = 0.0141 and p = 0.0314 respectively). In contrast, the CC-genotype was associated with elevated low density lipoprotein cholesterol (LDLc) and total cholesterol (TC) in individuals at higher risk for CVD (plaque positive) (p = 0.0396; p = 0.0363 respectively). Our study shows a functional effect of a promoter single-nucleotide polymorphism (SNP) in IL32 on lipid profiles in RA patients and individuals, suggesting a possible protective role of this SNP against CVD.

CNPQ No curso do desenvolvimento da teoria e da crítica literária, até o momento em que se torna um dos conceitos-chave do movimento romântico, a imaginação passa por diversas reformulações, que ora a situam na gênese da obra artística, ora a classificam como um de seus atributos. A expressão da faculdade imaginativa no romantismo brasileiro, e particularmente na dramaturgia romântica, não deixa de aportar em si divergências análogas, além de outras que lhe são próprias. Transitando entre a negação e a afirmação, a imaginação é muitas vezes referida como uma controversa faculdade ou potência de imitação, repetição e memória, em parte submissa a outras instâncias, como a razão, a história, a linha narrativa ou o conflito dramático, como um excesso e até mesmo como um distúrbio mental. Ela, porém, não deixa de ser percebida pelos escritores brasileiros como um importante elemento da concepção de obras artísticas, mesmo naquelas de fortes traços descritivos, dotada de certo grau de autonomia e passível de ser expandida pelo trabalho criativo. Para investigar os sentidos que a imaginação recebe no Brasil, tomamos de empréstimo a definição de Antonio Candido (1981), relativa à formação da literatura brasileira como síntese, compreendendo também como sintéticos os conceitos que dela fazem parte. Assim, lançamos-nos à busca das heranças culturais recebidas do setecentos e do oitocentos como bases que se interpenetram para formar os sentidos de imaginação no romantismo no Brasil; às transições e ressignificações pelas quais a imaginação passa quando em contato com outras culturas literárias; por fim, a uma tentativa de síntese, na qual verificamos os sentidos de imaginação presentes na linguagem literária e na crítica teatral. Au cours du développement de la théorie et de la critique littéraire, jusqu’à se transformer en un concept-clé du mouvement romantique, l’imagination subit plusieurs reformulations, qui soit la situent dans la genèse de l’œuvre artistique, soit la classent comme l’un de ses attributs. L’expression de la faculté imaginative dans le romantisme brésilien, et tout particulièrement dans la dramaturgie romantique, présente toujours en son sein quelques divergences analogues, ainsi que d’autres qui lui sont propres. En voyageant entre la négation et l’affirmation, l’imagination est bien souvent décrite comme une faculté controversée ou encore comme une puissance d’imitation, de répétition et de mémoire en partie soumise à d’autres instances, tels que la raison, l’histoire, la ligne narrative ou le conflit dramatique, comme un excès voire même comme un trouble mental. Cependant, elle continue à être considérée par les écrivains brésiliens comme un élément important de la conception d’œuvres artistiques, même pour celles contenant de forts traits descriptifs, dotée d’un certain degré d’autonomie et passible d’être répandue par le travail de création. Pour rechercher les sens dont l’imagination s’imprègne au Brésil, nous avons emprunté la définition d’Antonio Candido (1981), relative à la formation de la littérature brésilienne comme synthèse, considérant aussi comme synthétiques les concepts qui en font parti. Ainsi, nous nous sommes lancés à la recherche des héritages culturels reçus du XVIIIème et du XIXème siècles et qui constituent les bases qui s’interpénètrent pour former les sens d’imagination dans le romantisme au Brésil; à la recherche des transitions et des resignifications par lesquelles l’imagination passe quand elle se trouve en contact avec d’autres cultures littéraires; enfin, dans une tentative de synthèse, dans laquelle nous pouvons vérifier les sens d’imagination présents dans le langage littéraire et dans la critique théâtrale.

The plant Crataegus oxyacantha L., Rosaceae, also known as white hawthorn or hawthorn, is originally native to Europe, North America and Asia, but can also be found in other continents and has been widely used due to

Contains fulltext : 170874.pdf (Publisher’s version ) (Closed access) While the role of Toll-like receptors (TLRs) has been investigated in murine models of tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis, the interaction between TLRs and Leishmania sp. has not been investigated in human cells. The aim of this study was to evaluate the involvement of TLR4 in cytokine production of human peripheral blood mononuclear cells (PBMCs) induced by L. braziliensis, and whether the parasite alters the expression of TLR4 on monocytes/macrophages. Amastigote forms were obtained from mice lesions and PBMCs were isolated from healthy donors. PBMCs were cultured in absence or presence of IFNgamma, TLR4 neutralizing antibodies, natural antagonist of TLR4 (Bartonella LPS), TLR4 agonist (E. coli LPS), and amastigote forms. The concentrations of tumor necrosis factor (TNFalpha) and interleukin 10 (IL-10) were assayed by ELISA and TLR4 expression by flow cytometry. Amastigotes forms of L. braziliensis induced TNFalpha and IL-10 production only in IFNgamma-primed PBMCs. The TNFalpha and IL-10 production was inhibited by TLR4 neutralization, both with anti-TLR4 antibodies and Bartonella LPS. Interestingly, addition of E. coli LPS further increased TNFalpha but not IL-10 production induced by L. braziliensis amastigotes. Amastigotes of L. braziliensis strongly reduced membrane TLR4 expression on monocytes/macrophages, apparently by internalization after the infection. The present study reveals that TLR4 drives the production of TNFalpha and IL-10 induced by L. braziliensis amastigotes and that the parasites decrease TLR4 expression on monocyte surface.

Introduction The central nucleus of amygdala plays an important role mediating fear and anxiety responses. It is known that oxytocin microinjections into the central nucleus of amygdala induce hypergrooming, an experimental model of compulsive behavior. We evaluated the behavioral and cardiorespiratory responses of conscious rats microinjected with oxytocin into the central nucleus of amygdala. Methods Male Wistar rats were implanted with guide cannulae into the central nucleus of amygdala and microinjected with oxytocin (0.5 µg, 1 µg) or saline. After 24 h, rats had a catheter implanted into the femoral artery for pulsatile arterial pressure measurement. The pulsatile arterial pressure was recorded at baseline conditions and data used for cardiovascular variability and baroreflex sensitivity analysis. Respiratory and behavioral parameters were assessed during this data collection session. Results Microinjections of oxytocin (0.5 µg) into the central nucleus of amygdala produced hypergrooming behavior but did not change cardiorespiratory parameters. However, hypergrooming evoked by microinjections of oxytocin (1 µg) into the central nucleus of amygdala was accompanied by increase in arterial pressure, heart rate and ventilation and augmented the power of low and high (respiratory-related) frequency bands of the systolic arterial pressure spectrum. No changes were observed in power of the low and high frequency bands of the pulse interval spectrum. Baroreflex sensitivity was found lower after oxytocin microinjections, demonstrating that the oxytocin-induced pressor response may involve an inhibition of baroreflex pathways and a consequent facilitation of sympathetic outflow to the cardiovascular system. Conclusions The microinjection of oxytocin (1 µg) into the central nucleus of amygdala not only induces hypergrooming but also changes cardiorespiratory parameters. Moreover, specific oxytocin receptor antagonism attenuated hypergrooming but did not affect pressor, tachycardic and ventilatory responses to oxytocin, suggesting the involvement of distinct neural pathways.