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The coronavirus disease 2019 (COVID-19) pandemic has put into evidence another pandemic – obesity. Currently, several studies have documented the association between obesity and COVID-19 severity. The mechanisms underlying the increased risk of complications and mortality in obese patients with COVID-19 are of diverse nature. Inflammation plays a central role in obesity. Metabolic alterations seen in obese patients are related to an inflammatory response, and several studies report elevated levels of circulating inflammatory cytokines in obese patients. Also, deregulated expression of adipokines, such as leptin and resistin, increase the expression of vascular adhesion molecule 1 and intercellular adhesion molecule 1 that contribute to increased vascular leukocyte adhesiveness and additional oxidative stress. Additionally, it is now recognized that the chronic impairment of systemic vascular endothelial function in patients with cardiovascular and metabolic disorders, including obesity, when intensified by the detrimental effects of SARS-CoV-2 over the endothelium, may explain their worse outcomes in COVID-19. In fact, vascular endothelial dysfunction may contribute to a unfavorable response of the endothelium to the infection by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic environment in obesity may also provide a link to the increased cardiovascular events in these patients.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has devastating effects on the population worldwide. Given this scenario, the extent of the impact of the disease on more vulnerable individuals, such as pregnant women, is of great concern. Although pregnancy may be a risk factor in respiratory virus infections, there are no considerable differences regarding COVID-19 severity observed between pregnant and nonpregnant women. In these circumstances, an emergent concern is the possibility of neurodevelopmental and neuropsychiatric harm for the offspring of infected mothers. Currently, there is no stronger evidence indicating vertical transmission of SARS-CoV-2; however, the exacerbated inflammatory response observed in the disease could lead to several impairments in the offspring’s brain. Furthermore, in the face of historical knowledge on possible long-term consequences for the progeny’s brain after infection by viruses, we must consider that this might be another deleterious facet of COVID-19. In light of neuroimmune interactions at the maternal-fetal interface, we review here the possible harmful outcomes to the offspring brains of mothers infected by SARS-CoV-2.

Background Malaria is one of the most critical global infectious diseases. Severe systemic inflammatory diseases, such as cerebral malaria, lead to the development of cognitive and behavioral alterations, such as learning disabilities and loss of memory capacity, as well as increased anxiety and depression. The consequences are profound and usually contribute to reduce the patient’s quality of life. There are no therapies to treat the neurological sequelae of cerebral malaria. Mesenchymal stromal cells (MSCs) may be an alternative, since they have been used as therapy for neurodegenerative diseases and traumatic lesions of the central nervous system. So far, no study has investigated the effects of MSC therapy on the blood-brain barrier, leukocyte rolling and adherence in the brain, and depression like-behavior in experimental cerebral malaria. Methods Male C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA, 1 × 106 PbA-parasitized red blood cells, intraperitoneally). At day 6, PbA-infected animals received chloroquine (25 mg/kg orally for seven consecutive days) as the antimalarial treatment and were then randomized to receive MSCs (1 × 105 cells in 0.05 ml of saline/mouse) or saline (0.05 ml) intravenously. Parasitemia, clinical score, and survival rate were analyzed throughout the experiments. Evans blue assay was performed at 6, 7, and 15 days post-infection (dpi). Behavioral tests were performed at 5 and 15 dpi. Intravital microscopy experiments and brain-derived neurotrophic factor (BDNF) protein expression analyses were performed at 7 dpi, whereas inflammatory mediators were measured at 15 dpi. In vitro, endothelial cells were used to evaluate the effects of conditioned media derived from MSCs (CMMSC) on cell viability by lactate dehydrogenase (LDH) release. Results PbA-infected mice presented increased parasitemia, adherent leukocytes, blood-brain barrier permeability, and reduced BDNF protein levels, as well as depression-like behavior. MSCs mitigated behavioral alterations, restored BDNF and transforming growth factor (TGF)-β protein levels, and reduced blood-brain barrier dysfunction and leukocyte adhesion in the brain microvasculature. In a cultured endothelial cell line stimulated with heme, CMMSC reduced LDH release, suggesting a paracrine mechanism of action. Conclusion A single dose of MSCs as adjuvant therapy protected against vascular damage and improved depression-like behavior in mice that survived experimental cerebral malaria.

Objectives Survivors of sepsis are frequently left with significant cognitive and behavioral impairments. These complications derive from nonresolving inflammation that persists following hospital discharge. To date, no study has investigated the effects of mesenchymal stromal cell therapy on the blood-brain barrier, astrocyte activation, neuroinflammation, and cognitive and behavioral alterations in experimental sepsis. Design Prospective, randomized, controlled experimental study. Setting Government-affiliated research laboratory. Subjects Male Swiss Webster mice (n = 309). Interventions Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. All animals received volume resuscitation (1 mL saline/mouse subcutaneously) and antibiotics (meropenem 10 mg/kg intraperitoneally at 6, 24, and 48 hours). Six hours after surgery, mice were treated with mesenchymal stromal cells IV (1 × 10 cells in 0.05 mL of saline/mouse) or saline (0.05 mL IV). Measurements and main results At day 1, clinical score and plasma levels of inflammatory mediators were increased in cecal ligation and puncture mice. Mesenchymal stromal cells did not alter clinical score or survival rate, but reduced levels of systemic interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1. At day 15, survivor mice completed a battery of cognitive and behavioral tasks. Cecal ligation and puncture mice exhibited spatial and aversive memory deficits and anxiety-like behavior. These effects may be related to increased blood-brain barrier permeability, with altered tight-junction messenger RNA expression, increased brain levels of inflammatory mediators, and astrogliosis (induced at day 3). Mesenchymal stromal cells mitigated these cognitive and behavioral alterations, as well as reduced blood-brain barrier dysfunction, astrocyte activation, and interleukin-1β, interleukin-6, tumor necrosis factor-α, and interleukin-10 levels in vivo. In cultured primary astrocytes stimulated with lipopolysaccharide, conditioned media from mesenchymal stromal cells reduced astrogliosis, interleukin-1β, and monocyte chemoattractant protein-1, suggesting a paracrine mechanism of action. Conclusions In mice who survived experimental sepsis, mesenchymal stromal cell therapy protected blood-brain barrier integrity, reduced astrogliosis and neuroinflammation, as well as improved cognition and behavior.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Background Metabolic syndrome (MS) is defined as a low-grade proinflammatory state in which abnormal metabolic and cardiovascular factors increase the risk of developing cardiovascular disease and neuroinflammation. Events, such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in MS may contribute to the direct or indirect activation of Toll-like receptors (TLRs), specifically TLR4, which is thought to be a major component of this syndrome. Activation of the innate immune response via TLR4 may contribute to this state of chronic inflammation and may be related to the neuroinflammation and neurodegeneration observed in MS. In this study, we investigated the role of TLR4 in the brain microcirculation and in the cognitive performance of high-fat diet (HFD)-induced MS mice. Methods Wild-type (C3H/He) and TLR4 mutant (C3H/HeJ) mice were maintained under a normal diet (ND) or a HFD for 24 weeks. Intravital video-microscopy was used to investigate the functional capillary density, endothelial function, and endothelial–leukocyte interactions in the brain microcirculation. Plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), adipokines and metabolic hormones were measured with a multiplex immunoassay. Brain postsynaptic density protein-95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the vessels, microglial activation and structural capillary density were evaluated by immunohistochemistry. Results The HFD-induced MS model leads to metabolic, hemodynamic, and microcirculatory alterations, as evidenced by capillary rarefaction, increased rolling and leukocyte adhesion in postcapillary venules, endothelial dysfunction, and less coverage of astrocytes in the vessels, which are directly related to cognitive decline and neuroinflammation. The same model of MS reproduced in mice deficient for TLR4 because of a genetic mutation does not generate such changes. Furthermore, the comparison of wild-type mice fed a HFD and a normolipid diet revealed differences in inflammation in the cerebral microcirculation, possibly related to lower TLR4 activation. Conclusions Our results demonstrate that TLR4 is involved in the microvascular dysfunction and neuroinflammation associated with HFD-induced MS and possibly has a causal role in the development of cognitive decline.

Anticoagulants are associated with clinical benefit against the 2019 coronavirus disease (COVID-19), preventing COVID-19 associated coagulopathy. Blood coagulation factor Xa (FXa) and SARS-CoV-2 major protease (Mpro) share over 80% homology at the three-dimensional protein level. Thus, it is worth interrogating whether there is crosstalk between inhibitors and substrates between these enzymes. Here, we found that the clinically-approved FXa inhibitor apixaban targets SARS-CoV-2 Mpro with a 21-fold higher potency than boceprevir (GC376). Apixaban displayed a non-competitive mechanism of inhibition towards Mpro, since it targets the enzyme/substrate complex and the allosteric site onto the viral protease. Enzymatic assays were further validated in infected Calu-3 cells, which reveal that apixaban decreases the production of infectious viral particles in a dose-dependent manner, with an inhibitory potency in the micromolar range. Our results are in line with the proposed early use of anticoagulants, including FXa inhibitors, to improve clinical outcome of COVID-19 patients. In this context, apixaban may display a dual mechanism of action by targeting FXa to prevent coagulopathy and, at some level, SARS-CoV-2 Mpro.

Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-β peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.

Some pro-inflammatory lipids derived from 1 lipooxygenase enzyme are potent neutrophil chemoattractant, a cell centrally involved in acute respiratory distress syndrome (ARDS); a syndrome lacking effective treatment. Considering the beneficial effects of the leukotriene receptor inhibitor, montelukast, on other lung diseases, whether montelukast attenuates inflammation in a mouse model of ARDS, and whether it reduces LPS stimulated activation of human neutrophils was investigated.Thirty-five C57Bl/6 mice were distributed into control (PBS)+24h, LPS+24h (10μg/mouse), control+48h, LPS+48h, and LPS 48h+Montelukast (10mg/kg). In addition, human neutrophils were incubated with LPS (1μg/mL) and treated with montelukast (10μM).Oral-tracheal administration of montelukast significantly attenuated total cells (P.05), macrophages (P.05), neutrophils (P.01), lymphocytes (P.001) and total protein levels in BAL (P.05), as well as IL-6 (P.05), CXCL1/KC (P.05), IL-17 (P.05) and TNF-α (P.05). Furthermore, montelukast reduced neutrophils (P.001), lymphocytes (P.01) and macrophages (P.01) in the lung parenchyma. In addition, montelukast restored BAL VEGF levels (P.05). LTB4 receptor expression (P.001) as well as NF-κB (P.001), a downstream target of LPS, were also reduced in lung parenchymal leukocytes. Furthermore, montelukast reduced IL-8 (P.001) production by LPS-treated human neutrophils.In conclusion, montelukast efficiently attenuated both LPS-induced lung inflammation in a mouse model of ARDS and in LPS challenged human neutrophils.

Trophic factors are involved in different cellular responses. Previously we demonstrated that IL-4 treatment induces an increase in retinal ganglion cell survival (RGCS) and regulates cholinergic differentiation of retinal cells in vitro. Data from literature show that IGF-1 also promotes RGCS, an effect mediated by PI-3K/AKT pathway. The aim of this study was to investigate the role of IGF-1 and IGF-1R on RGCS mediated by IL-4 treatment and the role of M1 acetylcholine receptors in this effect. Here we show that the effect of IL-4 on RGCS depends on IGF-1 and IGF-1R activation, the PI-3K/AKT and NFkB intracellular pathways and depends on M1 mAChRs activation. IGF-1 increases the levels of M1 mAChRs in 15min, 45min, 24 h and 48 h in mixed retinal cells culture, modulates the levels of IL-4, pIGF-1R, IGF-1R. IL-4 modulates IGF-1, pIGF-1R and IGF-1R levels in different time intervals. These results put in evidence a crosstalk between IL-4 and IGF-1 and a role of M1 mAChRs, IGF-1 and IGF-1R in RGCS mediated by IL-4.

Fatty acids are fundamental as energy and structural source to the human cells. They are not usually found free in human circulation. Alteration in fatty acids metabolism is linked to diseases such as diabetes, preeclampsia, heart disease, and some infectious diseases. Increased levels of non-esterified fatty acids (NEFA) may cause cell dysfunction and lipotoxicity. Since physiologically fatty acids are transported bound to albumin, we propose here a simple and cheap test that consists of albumin isoelectric focusing determination to measure the potential systemic NEFA cytotoxicity. For validation of this method, albumin isoelectric focusing in 51 serum samples from 40 critically ill patients and 11 controls was compared with NEFA/albumin ratios measured by HPLC. We called this approach an albumin saturation test. This test may indicate to physicians the potential NEFA lipotoxicity guiding them throughout better patient management. The albumin saturation test can point out serum albumin-NEFA saturation through a cheap assay that could be performed by any care facility.

An insult can trigger a protective response or even cell death depending on different factors that include the duration and magnitude of the event and the ability of the cell to activate protective intracellular signals, including inflammatory cytokines. Our previous work showed that the treatment of Lister Hooded rat retinal cell cultures with 50 ng/mL phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, increases the survival of retinal ganglion cells (RGCs) kept in culture for 48 h after axotomy. Here we aim to analyze how PMA modulates the levels of TNF-α and IL-1β (both key inflammatory mediators) and the impact of this modulation on RGCs survival. We hypothesize that the increase in RGCs survival mediated by PMA treatment depends upon modulation of the levels of IL-1β and TNF-α. The effect of PMA treatment was assayed on cell viability, caspase 3 activation, TNF-α and IL-1β release and TNF receptor type I (TNFRI) and TNF receptor type II (TNFRII) levels. PMA treatment increases IL-1β and TNF-α levels in 15 min in culture and increases the release of both cytokines after 30 min and 24 h, respectively. Both IL-1β and TNF-α levels decrease after 48 h of PMA treatment. PMA treatment also induces an increase in TNFRII levels while decreasing TNFRI after 24 h. PMA also inhibited caspase-3 activation, and decreased ROS production and EthD-1/calcein ratio in retinal cell cultures leading to an increase in cell viability. The neutralization of IL-1β (anti-IL1β 0,1ng/mL), the neutralization of TNF-α (anti-TNF-α 0,1ng/mL) and the TNF-α inhibition using a recombinant soluble TNFRII abolished PMA effect on RGCs survival. These data suggest that PMA treatment induces IL1β and TNF-α release and modulation of TNFRI/TNFRII expression promoting RGCs survival after axotomy.

Human leptospirosis is an acute infectious zoonosis presenting specific lipid disorders. Previous in vitro studies showed both leptospira glycolipoprotein endotoxin, and high oleic acid levels were associated with Na/K-ATPase inhibition that is amplified by the reduction of circulating albumin levels. In this study, we aimed to investigate the relationship of oleic acid/albumin (OA/A) molar ratio and clinical outcomes in Leptospirosis. Through a prospective observational cohort study employing high-performance liquid chromatography (HPLC) we sequentially determined serum concentrations of nonesterified fatty acids (NEFA) and albumin in twenty-eight patients with severe leptospirosis since their hospital admission. Twenty patients recovered, and eight died. Data was distributed in two groups according to clinical outcomes. Oleic acid/albumin molar ratios (OA/A), initial samples, were higher than those in healthy donors. The ratio OA/A, however, persisted high in dying patients, whereas patients who survived had a reduction matching to healthy donors. Biochemical alterations suggest that cure is correlated to the reestablishment of the OA/A molar ratio, while fatal outcomes related to persisting OA/A imbalances. Analysis by receiver operating characteristic (ROC) showed the area under the curve of 0.864 and the cutoff value of 0.715 being associated with a high odds ratio. Lipid analysis from patients with leptospirosis had an acute high serum OA/A molar ratio, and sustained imbalance has a high odds ratio and strong correlation with mortality., Leptospirosis clinical outcome; Acute lipotoxicity; Lipidome; Oleic acid/albumin; Na/K-ATPase.

Background Microvascular dysfunction, serum cytokines and chemokines may play important roles in pathophysiology of coronavirus disease 2019 (COVID-19), especially in severe cases. Methods Patients with COVID-19 underwent non-invasive evaluation of systemic endothelium-dependent microvascular reactivity - using laser Doppler perfusion monitoring in the skin of the forearm - coupled to local thermal hyperemia. Maximal microvascular vasodilatation (44 °C thermal plateau phase) was used as endpoint. A multiplex biometric immunoassay was used to assess a panel of 48 serum cytokines and chemokines. Severe COVID-19 (S-COVID) was defined according to WHO criteria, while all other cases of COVID-19 were considered mild to moderate (M-COVID). A group of healthy individuals who tested negative for SARS-CoV-2 served as a control group and was also evaluated with LDPM. Results Thirty-two patients with COVID-19 (25% S-COVID) and 14 controls were included. Basal microvascular flow was similar between M-COVID and controls (P = 0.69) but was higher in S-COVID than in controls (P = 0.005) and M-COVID patients (P = 0.01). The peak microvascular vasodilator response was markedly decreased in both patient groups (M-COVID, P = 0.001; S-COVID, P, Highlights • During acute COVID-19, endothelium-dependent microvascular vasodilator responses are reduced. • Impaired systemic microvascular vasodilation is more evident in severe vs mild-moderate COVID-19. • Increased levels of cytokines and chemokines are associated with COVID-19 severity.

Background The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring. Methods Pregnant mice at the 14th embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 108 CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1β, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and β-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60. Results Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring. Conclusion These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter.

Background: Coronavirus disease 2019 (COVID-19) associated- severe acute respiratory distress syndrome (ARDS) patients may require prolonged mechanical ventilation, thus resulting in lung fibrosis and high fatality rates. Several therapies have been developed in patients with pneumonia requiring oxygen therapy as well as during the early course of invasive mechanical ventilation. Mesenchymal stromal cells (MSCs) may have a role in controlling the hyperinflammatory response seen in such cases and prevent aggravation or increase/accelerate recovery. While MSC-based therapies have been studied mostly in patients that did not require invasive ventilation or during the first hours of tracheal intubation, to date the potential of MSC therapy to treat advanced-stage of severe/critical COVID-19 cases has not been extensively studied. Methods: This is a case report of a 30-year-old male patient who presented progressive clinical deterioration of COVID-19 in ICU after 21-day admission and 14 days with invasive mechanical ventilation. The first symptom onset was 35 days before MSC therapy. The patient was treated with allogenic human umbilical cord-derived MSCs [5 x 107 (2 doses 2 days interval)].Results: No serious adverse events attributed to MSC administration were observed during and after the procedure. Oxygenation (PaO2/FiO2 ratio) and the need for vasoactive drugs improved. Chest CT scan imaging, which showed signs of bilateral and peripheral ground-glass, consolidation as well as fibrosis, improved significantly during the time course of the disease. Patient was discharged 13 days after cell therapy. Cytokine analysis demonstrated modulation of different mediators accompanied by modulation of different cell populations in peripheral blood, including a reduction in inflammatory monocytes, increased frequency of patrolling monocytes, CD4+ lymphocytes and type 2 classical dendritic cells (cDC2). Conclusion: This study described for the first time the effects of MSC therapy in a patient at late stage COVID-19 associated severe lung injury and fibrosis. Therefore, further clinical trials should be design assessing the efficacy of MSC therapy in ARDS patients undergoing prolonged mechanical ventilation due to COVID-19.

Malaria is caused by Plasmodium infection and remains a serious public health problem worldwide, despite control efforts. Malaria can progress to severe forms, affecting multiple organs, including the brain causing cerebral malaria (CM). CM is the most severe neurological complication of malaria, and cognitive and behavior deficits are commonly reported in surviving patients. The number of deaths from malaria has been reducing in recent years, and as a consequence, neurological sequelae have been more evident. Neurological damage in malaria might be related to the neuroinflammation, characterized by glia cell activation, neuronal apoptosis and changes in the blood-brain barrier (BBB) integrity. The neurovascular unit (NVU) is responsible for maintaining the homeostasis of the BBB. Endothelial and pericytes cells in the cerebral microvasculature and neural cells, as astrocytes, neurons, and microglia, compose the NVU. The NVU can be disturbed by parasite metabolic products, such as heme and hemozoin, or cytokines that can promote activation of endothelial and glial cells and lead to increased BBB permeability and subsequently neurodegeneration. In this review, we will approach the main changes that happen in the cells of the NVU due to neuroinflammation caused by malaria infection, and elucidate how the systemic pathophysiology is involved in the onset and progression of CM.

Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally. Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-α- and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14–16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normal-sucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-α and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND- or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease.

Background Brain circulation disorders such as chronic cerebral hypoperfusion have been associated with a decline in cognitive function during the development of dementia. Astrocytes together with microglia participate in the immune response in the CNS and make them potential sentinels in the brain parenchyma. In addition, astrocytes coverage integrity has been related to brain homeostasis. Currently, physical exercise has been proposed as an effective intervention to promote brain function improvement. However, the neuroprotective effects of early physical exercise on the astrocyte communication with the microcirculation and the microglial activation in a chronic cerebral hypoperfusion model are still unclear. The aim of this study was to investigate the impact of early intervention with physical exercise on cognition, brain microcirculatory, and inflammatory parameters in an experimental model of chronic cerebral hypoperfusion induced by permanent bilateral occlusion of the common carotid arteries (2VO). Methods Wistar rats aged 12 weeks were randomly divided into four groups: Sham-sedentary group (Sham-Sed), Sham-exercised group (Sham-Ex), 2VO-sedentary group (2VO-Sed), and 2VO-exercised group (2VO-Ex). The early intervention with physical exercise started 3 days after 2VO or Sham surgery during 12 weeks. Then, the brain functional capillary density and endothelial-leukocyte interactions were evaluated by intravital microscopy; cognitive function was evaluated by open-field test; hippocampus postsynaptic density protein 95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the capillaries, microglial activation, and structural capillary density were evaluated by immunohistochemistry. Results Early moderate physical exercise was able to normalize functional capillary density and reduce leukocyte rolling in the brain of animals with chronic cerebral hypoperfusion. These effects were accompanied by restore synaptic protein and the improvement of cognitive function. In addition, early moderate exercise improves astrocytes coverage in blood vessels of the cerebral cortex and hippocampus, decreases microglial activation in the hippocampus, and improves structural capillaries in the hippocampus. Conclusions Microcirculatory and inflammatory changes in the brain appear to be involved in triggering a cognitive decline in animals with chronic cerebral ischemia. Therefore, early intervention with physical exercise may represent a preventive approach to neurodegeneration caused by chronic cerebral hypoperfusion.

The Mediterranean diet, rich in olive oil, is beneficial, reducing the risk of cardiovascular diseases and cancer. Olive oil is mostly composed of the monounsaturated fatty acid omega-9. We showed omega-9 protects septic mice modulating lipid metabolism. Sepsis is initiated by the host response to infection with organ damage, increased plasma free fatty acids, high levels of cortisol, massive cytokine production, leukocyte activation, and endothelial dysfunction. We aimed to analyze the effect of omega-9 supplementation on corticosteroid unbalance, inflammation, bacterial elimination, and peroxisome proliferator-activated receptor (PPAR) gamma expression, an omega-9 receptor and inflammatory modulator. We treated mice for 14 days with omega-9 and induced sepsis by cecal ligation and puncture (CLP). We measured systemic corticosterone levels, cytokine production, leukocyte and bacterial counts in the peritoneum, and the expression of PPAR gamma in both liver and adipose tissues during experimental sepsis. We further studied omega-9 effects on leukocyte rolling in mouse cremaster muscle-inflamed postcapillary venules and in the cerebral microcirculation of septic mice. Here, we demonstrate that omega-9 treatment is associated with increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the proinflammatory cytokines TNF-αand IL-1βin peritoneal lavage fluid of mice with sepsis. Omega-9 treatment also decreased systemic corticosterone levels. Neutrophil migration from circulation to the peritoneal cavity and leukocyte rolling on the endothelium were decreased by omega-9 treatment. Omega-9 also decreased bacterial load in the peritoneal lavage and restored liver and adipose tissue PPAR gamma expression in septic animals. Our data suggest a beneficial anti-inflammatory role of omega-9 in sepsis, mitigating leukocyte rolling and leukocyte influx, balancing cytokine production, and controlling bacterial growth possibly through a PPAR gamma expression-dependent mechanism. The significant reduction of inflammation detected after omega-9 enteral injection can further contribute to the already known beneficial properties facilitated by unsaturated fatty acid-enriched diets.

Antimalarial interventions mostly rely upon drugs, as chloroquine. However, plasmodial strains resistant to many drugs are constantly reported, leading to an expansion of malaria cases. Novel approaches are required to circumvent the drug resistance issue. Here, we describe the antimalarial potential of the chloroquine analogue 2-[[2-[(7-chloro-4-quinolinyl)amino]ethyl]amino] ethanol (PQUI08001/06). We observed that PQUI08001/06 treatment reduces parasitemia of both chloroquine-resistant and -sensitive strains of Plasmodium falciparum in vitro and P. berghei in vivo. Our data suggests that PQUI08001/06 is a potential antimalarial therapeutic alternative approach that could also target chloroquine-resistant plasmodial strains.

Background Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. Methods Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. Results Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1β and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation. Conclusions Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments. Electronic supplementary material The online version of this article (10.1186/s12974-018-1059-y) contains supplementary material, which is available to authorized users.

Background Sepsis is a systemic inflammatory host-response against a pathogen; it is the largest cause of admission to intensive care units (ICUs) in the United States. Sepsis-associated encephalopathies (SAEs) are neurological complications that occur during or after sepsis events. SAE causes long-term neurological consequences affecting memory, cognition and mood. Currently, there is no prevention or treatment for neurological damage resulting from SAEs. Thus, investigating new therapies is necessary. Both clinical and experimental studies have been show the effects of cell therapy in neurodegenerative diseases. Indeed, the immunomodulatory capacity of mesenchymal stromal cells (MSCs) is well established. Considering that, the aim of the present study was to evaluate the effects of MSC therapy on blood-brain barrier (BBB) maintenance, astrocyte activation, cognitive and behavioral damage in an experimental model of sepsis. Methods Male adult Swiss mice underwent cecal ligation and puncture (CLP) surgery for sepsis induction and sham-operated animals were used as control. Six hours after surgery, mice were treated with MSC intravenously (1 × 105 cells in 0.05 mL of saline/mouse) or saline. For in vitro, analysis cultured astrocytes were stimulated with lipopolysaccharide (LPS) (1μg/ ml). After 24 hours, cells were washed to eliminated residual LPS and then treated with conditioned media from MSCs (CM-MSCs). Results MSC therapy led to a reduction in systemic levels of IL-1β, IL-6, and MCP-1, a decrease in cortical and hippocampal cytokine levels, a reduction in astrogliosis (evaluated by immunofluorescence) and BBB protection (evaluated by Evans Blue Dye Assay). In cultured astrocytes stimulated with LPS, CM-MSCs reduced astrogliosis at 24h, suggesting a paracrine mechanism of action. These results might be associated with an improvement in spatial memory (Morris Water Maze test), aversive memory (fear-conditioned test) and anxiety-like behavior (Elevated plus maze test). Conclusion A single dose- therapy with MSC led to an improvement in cognitive damage, behavioral impairments, protection of the BBB, reduction in local levels of cytokines and astrogliosis and these effects might be associated with a decrease in systemic levels of inflammatory mediators.

Acute brain dysfunction is a frequent condition in sepsis patients and is associated with increased mortality and long-term neurocognitive consequences. Impaired memory and executive function are common findings in sepsis survivors. Although neuroinflammation and blood-brain barrier dysfunction have been associated with acute brain dysfunction and its consequences, no specific treatments are available that prevent cognitive impairment after sepsis. Experimental sepsis was induced in Swiss Webster mice by intraperitoneal injection of cecal material (5mg/kg, 500μL). Control groups (n=5/group each experiment) received 500μL of saline. Support therapy recover (saline 0.9%, 1mL and imipenem 30mg/kg) were applied (6, 24 and 48h post injection, n=5-10/group, each experiment), together or not with additive orally treatment with statins (atorvastatin/simvastatin 20mg/kg b.w.). Survival rate was monitored at 6, 24 and 48h. In a setting of experiments, animals were euthanized at 6 and 24h after induction for biochemical, immunohistochemistry and intravital analysis. Statins did not prevented mortality in septic mice, however survivors presented lower clinical score. At another setting of experiments, after 15days, mice survivors from fecal supernatant peritoneal sepsis presented cognitive dysfunction for contextual hippocampal and aversive amygdala-dependent memories, which was prevented by atorvastatin/simvastatin treatment. Systemic and brain tissue levels of proinflammatory cytokines/chemokines and activation of microglial were lower in septic mice treated with statins. Brain lipid peroxidation and myeloperoxidase levels were also reduced by statins treatment. Intravital examination of the brain vessels of septic animals revealed decreased functional capillary density and increased rolling and adhesion of leukocytes, and blood flow impairment, which were reversed by treatment with statins. In addition, treatment with statins restored the cholinergic vasodilator response due to sepsis. Taken together, these data demonstrated that statins reverse microvascular dysfunction and reduce neuroinflammation during sepsis, preventing the development of long-term cognitive decline.

Mansonic schistosomiasis is a disease caused by the trematode Schistosoma mansoni, endemic to tropical countries. S. mansoni infection induces the formation of granulomas and potent polarization of Th2-type immune response. There is great interest in understanding the mechanisms used by this parasite that causes a modulation of the immune system. Recent studies from our group demonstrated that lipids of S. mansoni, including lysophosphatidylcholine (LPC) have immunomodulatory activity. In the present study, our aim was to investigate the role of lipids derived from S. mansoni in the activation and polarization of macrophages and to characterize the mechanisms involved in this process. Peritoneal macrophages obtained from wild type C57BL/6mice or bone marrow derived macrophages were stimulated in vitro with lipids extracted from adult worms of S. mansoni. We demonstrated that total schistosomal-derived lipids as well as purified LPC induced alternatively activated macrophages/M2 profile observed by increased expression of arginase-1, mannose receptor, Chi3l3, TGFβ and production of IL-10 and PGE2 24h after stimulation. The involvement of the nuclear receptor PPARγ in macrophage response against LPC was investigated. Through Western blot and immunofluorescence confocal microscopy we demonstrated that schistosomal-derived LPC induces increased expression of PPARγ in macrophages. The LPC-induced increased expression of arginase-1 were significantly inhibited by the PPAR-γ antagonist GW9662. Together, these results demonstrate an immunomodulatory role of schistosomal-derived LPC in activating macrophages to a profile of the type M2 through PPARγ-dependent mechanisms, indicating a novel pathway for macrophage polarization triggered by parasite-derived LPC with potential implications to disease pathogenesis.

Many ARDS survivors have evidence of pulmonary fibrosis after ARDS clinical resolution. A clinically relevant animal model is essential for assessing disease progression, since most ALI models using LPS do not evolve with persistent inflammation, limiting the understanding of which factors determine adequate repair or progression to fibrosis in the advanced stages of the disease. In this study, we proposed a model of ALI that associates LPS with high O2 concentration, aimed to induce a severe pulmonary lesion with chronic evolution to lung fibrosis. Mice were divided into 6 groups: CTR-4h, CTR-3w, LPS-4h, LPS-3w, LPS+O2-4h and LPS+O2-3w. LPS groups received 200µg of LPS IT and were euthanized after 4 hours or 3 weeks. LPS+O2 groups received 200µg of LPS IT+72 hours of O2 80% and were euthanized after 4 hours or 3 weeks. We analyzed lung tissue inflammation, pulmonary cytokine levels in BALF, the expression of pulmonary SOD-2 activity, and the deposition of collagen and elastic fibers in the pulmonary parenchyma. The LPS ALI model showed high number of neutrophils in lung tissue, and high levels of IL-6, KC and TNF in BALF in the LPS-4h group, and high levels of IL-4 and TGF-s in the LPS-3w group. Parenchymal remodeling was not observed in the LPS groups. The LPS+O2 ALI model showed high number of neutrophils and high levels of IL-6 and IL-10 in both 4h and 3w groups, high levels of IL-1s and KC in LPS+O2-4h group, high expression of SOD-2 in both 4h and 3w groups, and high content of collagen and elastic fibers in lung tissue in the LPS+O2-3w group. Our results show that the LPS+O2 model induced an acute lung injury with persistent pulmonary inflammation and remodeling after 3 weeks. Funding: CAPES, CNPq.

Asthma is a chronic disease with impacts on public health. It affects the airways causing pulmonary inflammation mediated by CD4 T cells type Th2, eosinophilia, mucus hypersecretion, and elevated IgE. The unbalance between cytokines and transcription factors is an important feature in asthma. Probiotics has gaining highlight as a therapy for chronic diseases. Thus, we investigate the Lactobacillus bulgaricus (Lb) effect in murine allergic asthma. BALB/c-mice were sensitized to ovalbumin (OA) on days 0 and 7 and were challenged from day 14-28 with OA. Mice received Lb seven days prior to sensitization and it was kept until day 28. The Lb attenuated the eosinophils infiltration, mucus and collagen secretion, IgE production, pro-inflammatory cytokines, TLR4 expression, GATA3, STAT6 and RORγt in lung. Otherwise, Lb increased the anti-inflammatory cytokines, the T-bet and foxp3. Finally, Lb attenuated the allergic asthma-induced inflammation and airway remodeling by interfering on Th1/Th2 cytokines and STAT6/T-bet transcription factors.

Sepsis is a complex inflammatory disorder believed to originate from an infection by any types of microbes and/or their products. It is the leading cause of death in intensive care units (ICUs) throughout the globe. The mortality rates depend both on the severity of infection and the host’s response to infection. Literature survey on pathobiology of sepsis in general and failure of more than hundred clinical trials conducted so far in search of a possible cure for sepsis resulted in the preparation of this manuscript. Sepsis lacks a suitable animal model that mimics human sepsis. However, based on the results obtained in animal models of sepsis, clinical trials conducted so far have been disappointing. Although involvement of multiple mediators and pathways in sepsis has been recognized, only few components are being targeted and this could be the major reason behind the failure of clinical trials. Inability to recognize a single critical mediator of sepsis may be the underlying cause for the poor therapeutic intervention of sepsis. Therefore, sepsis is still considered as a disease—in search of cure.

COPD is a prevalent lung disease with significant impacts on public health. Affected airways exhibit pulmonary neutrophilia and consequent secretion of pro-inflammatory cytokines and proteases, which result in lung emphysema. Probiotics act as nonspecific modulators of the innate immune system that improve several inflammatory responses. To investigate the effect ofLactobacillus rhamnosus (Lr)on cigarette smoke (CS)-induced COPD C57Bl/6 mice were treated withLrduring the week before COPD induction and three times/week until euthanasia. Forin vitroassays, murine bronchial epithelial cells as well as human bronchial epithelial cells exposed to cigarette smoke extract during 24 hours were treated withLr1 hour before CSE addition.Lrtreatment attenuated the inflammatory response both in the airways and lung parenchyma, reducing neutrophilic infiltration and the production of pro-inflammatory cytokines and chemokines. Also, Lr-treated mice presented with lower metalloproteases in lung tissue and lung remodeling. In parallel to the reduction in the expression of TLR2, TLR4, TLR9, STAT3, and NF-κB in lung tissue,Lrincreased the levels of IL-10 as well as SOCS3 and TIMP1/2, indicating the induction of an anti-inflammatory environment. Similarly, murine bronchial epithelial cells as well as human bronchial epithelial cells (BEAS) exposed to CSE produced pro-inflammatory cytokines and chemokines, which were inhibited byLrtreatment in association with the production of anti-inflammatory molecules. Moreover, the presence of Lr also modulated the expression of COPD-associated transcription found into BALF of COPD mice group, i.e.,Lrdownregulated expression of NF-κB and STAT3, and inversely upregulated increased expression of SOCS3. Thus, our findings indicate thatLrmodulates the balance between pro- and anti-inflammatory cytokines in human bronchial epithelial cells upon CS exposure and it can be a useful tool to improve the lung inflammatory response associated with COPD.

Background: Malaria-associated (MA) ARDS has 80% mortality rate and no specific treatment. Aim: To evaluate the effects of acetylsalicylic acid (ASA) and combined therapy with dihidroarthemisinin (DHA) on experimental MA-ARDS. Methods: C57BL/6 mice were randomly divided in control (C) and infected (Pb; 104 Plasmodium berghei NK65 infected erythrocyte) groups, and treated on day 8 orally with ASA (100mg/kg) or saline, and vehicle (DMSO) or DHA (3mg/kg), ip. Results: Pb-DMSO and Pb-ASA groups showed higher lung static elastance (Est) (65±12cmH2O.ml-1; 61±14cmH2O.ml-1, respectively), resistive (P1) (0.6±0.1cmH2O; 0.5±0.1cmH2O, respectively) and viscoelastic (P2) (1.1±0.1cmH2O; 0.9±0.1cmH2O, respectively) pressures than C group (Est 38±14cmH2O.ml-1; P1 0.4±0.1cmH2O; P2 0.7±0.1cmH2O). Pb-DMSO [2.5(0.3/6)g/l] but not Pb-ASA [0.5(0.14/2.3)g/l] nor Pb-ASA+DHA [0.5 (0.08/2.5)g/l] showed higher protein levels on bronchoalveolar lavage (BAL) compared to C [0.08(0.05/0.1)g/l]. Pb-ASA (25%) presented similar survival rate to Pb-DMSO (27%), 78% of ASA+DHA and all Pb-DHA group survived until day 15. DHA [11.5±7.8 10³/mm³] and ASA+DHA [13±7.8 10³/mm³] treatment led to reduction of leucocytes on blood compared to Pb-DMSO [118±37 10³/mm³]. MCP-1 levels on BAL were higher in Pb-DMSO and Pb-DHA, but not in ASA nor ASA+DHA, compared to C. Pb-DMSO group presented thrombocytopenia [192±40 10³/mm³], without recovery after 7 days of DHA [376±151 10³/mm³] nor ASA+DHA [312±139 10³/mm³] treatment. Conclusion: Although ASA treatment do not lead to any deleterious effects in lung mechanics it may be not recommended in endemic areas, since it might me related to increased mortality rate even combined with anti-malarial treatment.

Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the αD subunit (αD-/-) of the αDβ2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P. berghei ANKA). To further identify mechanisms involved in the protective effect of αD deletion in this model of severe malaria we examined wild type C57BL/6 (WT) and αD-/- mice after P. berghei ANKA infection and found that vessel plugging and leukocyte infiltration were significantly decreased in the brains of αD-/- animals. Intravital microscopy demonstrated decreased rolling and adhesion of leukocytes in cerebral vessels of αD-/- mice. Flow cytometry analysis showed decreased T-lymphocyte accumulation in the brains of infected αD-/- animals. Evans blue dye exclusion assays demonstrated significantly less dye extravasation in the brains of αD-/- mice, indicating preserved blood-brain barrier integrity. WT mice that were salvaged from P. berghei ANKA infection by treatment with chloroquine had impaired aversive memory, which was not observed in αD-/- mice. We conclude that deletion of integrin αDβ2 alters the natural course of experimental severe malaria, demonstrating previously unrecognized activities of a key leukocyte integrin in immune-inflammatory responses that mediate cerebral involvement.

The present study was aimed to investigate the phototherapy effect with low-level laser on human bronchial epithelial cells activated by cigarette smoke extract (CSE). Phototherapy has been reported to actuate positively for controlling the generation/release of anti-inflammatory and pro-inflammatory mediators from different cellular type activated by distinct stimuli. It is not known whether the IL-8 and IL-10 release from CSE-stimulated human bronchial epithelium (BEAS) cells can be influenced by phototherapy. Human bronchial epithelial cell (BEAS) line was cultured in a medium with CSE and irradiated (660 nm) at 9 J. Apoptosis index was standardized with Annexin V and the cellular viability was evaluated by MTT. IL-8, IL-10, cAMP, and NF-κB were measured by ELISA as well as the Sp1, JNK, ERK1/2, and p38MAPK. Phototherapy effect was studied in the presence of mithramycin or the inhibitors of JNK or ERK. The IL-8, cAMP, NF-κB, JNK, p38, and ERK1/2 were downregulated by phototherapy. Both the JNK and the ERK inhibitors potentiated the phototherapy effect on IL-8 as well as on cAMP secretion from BEAS. On the contrary, IL-10 and Sp1 were upregulated by phototherapy. The mithramycin blocked the phototherapy effect on IL-10. The results suggest that phototherapy has a dual effect on BEAS cells because it downregulates the IL-8 secretion by interfering with CSE-mediated signaling pathways, and oppositely upregulates the IL-10 secretion through of Sp1 transcription factor. The manuscript provides evidence that the phototherapy can interfere with MAPK signaling via cAMP in order to attenuate the IL-8 secretion from CSE-stimulated BEAS. In addition, the present study showed that phototherapy effect is driven to downregulation of the both the IL-8 and the ROS secretion and at the same time the upregulation of IL-10 secretion. Besides it, the increase of Sp-1 transcription factor was crucial for laser effect in upregulating the IL-10 secretion. The dexamethasone corticoid produces a significant inhibitory effect on IL-8 as well as ROS secretion, but on the other hand, the corticoid blocked the IL-10 secretion. Taking it into consideration, it is reasonable to suggest that the beneficial effect of laser therapy on lung diseases involves its action on unbalance between pro-inflammatory and anti-inflammatory mediators secreted by human bronchial epithelial cells through different signaling pathway.

β2 integrins are critical in host defense responses to invading pathogens and inflammation. Previously, we reported that genetic deficiency of integrin αDβ2 in mice altered outcomes in experimental systemic infections including accelerated mortality in animals infected with Salmonella enterica serovar Typhimurium. Here, we show that deficiency of αDβ2 results in impaired accumulation of leukocytes in response to peritoneal infection by S. Typhimurium, impaired pathogen clearance in vivo, defective bacterial elimination by cultured peritoneal macrophages, and enhanced pyroptosis, a cell death process triggered by Salmonella. Salmonella-infected animals deficient in αDβ2 had increased levels of peritoneal cytokines in addition to other markers of pyroptosis, which may contribute to inflammatory injury and increased mortality in the context of impaired bacterial killing. These observations indicate important contributions of leukocyte integrins to the host response in experimental Salmonella infection and reveal previous activities of αDβ2 in bacterial infection.

Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-α-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose-dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side.

Leptin directly activates macrophages and lymphocytes, but the role of leptin in neutrophil activation and migration is still controversial. Here, we investigate the in vivo mechanisms of neutrophil migration induced by leptin. The intraperitoneal injection of leptin (1 mg/kg) induces a time- and concentration-dependent neutrophil influx. We did not observe the enhancement of lipid bodies/droplets in neutrophils, after leptin treatment, as we had observed previously in peritoneal macrophages. The participation of leukotriene B4 (LTB4) in neutrophil recruitment triggered by leptin was investigated using different strategies. Leptin-induced neutrophil recruitment occurs both in the absence of 5-lipoxygenase activity in 5-lipoxygenase (5-LO)-/- mice and after the administration of either 5-LO inhibitor (Zileuton) or the LTB4 receptor antagonist (U-75302). Moreover, no direct induction of LTB4 by leptin could be observed. Neutrophil influx could not be prevented by the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, contrasting with the leptin-induced signaling for lipid body formation in macrophage that is mTOR-dependent. Leptin administration led to tumor necrosis factor-alpha (TNFα) production by the peritoneal cells both in vivo and in vitro. In addition, neutrophil recruitment was inhibited in tumor necrosis factor receptor 1 (TNFR1-/-) mice, indicating a role for TNF in leptin-induced neutrophil recruitment to the peritoneal cavity. Leptin-induced neutrophil influx was PI3Kγ-dependent, as it was absent in PI3Kγ-/- mice. Accordingly, leptin induced the peritoneal cells to produce CXCL1, both in vivo and in vitro, and the neutrophil influx was ablated after using an antibody against CXCL1. Our results establish TNFα/TNFR1- and CXCL1-dependent signaling as important pathways for leptin-induced neutrophil migration in vivo.

Objective: We investigated the acute effects of SIM on cerebral microvascular rarefaction and dysfunction in SHRs. Methods: Male WKY and SHRs were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL, treated with 0.9% saline; and WKY+SIM and SHR+SIM, treated with SIM (30 mg/kg/d) for 3 days by gavage. Cerebral FCD was assessed by intravital fluorescence videomicroscopy. mCBF before and after administration within the cranial window of angiotensin II (1 μmol L−1) was investigated using laser speckle contrast imaging. Results: Cerebral FCD was reduced in SHR-CTL compared to WKY-CTL (P < .05). SIM increased cerebral FCD in SHRs compared to SHR-CTL (P < .05). The mCBF was reduced in SHR-CTL compared to WKY-CTL (P < .05), and SIM increased mCBF compared with SHR-CTL (P < .05). Angiotensin II elicited a reduction of mCBF in SHR-CTL and increased mCBF in WKY-CTL (SHR-CTL -13.53 ± 2% vs WKY-CTL +13.74 ± 4%; P < .001), which was attenuated in SHRs treated with SIM (SHR+SIM -6.7 ± 1% vs SHR-CTL -13.53 ± 2%; P < .01). Conclusions: The antihypertensive effect of SIM is associated with an improvement in cerebral microvascular perfusion and capillary density that may help to prevent hypertension-induced cerebrovascular damage independent of cholesterol-lowering.