The non-pathogenic protozoon Leishmania tarentolae interferes with the activation of NLRP3 inflammasome in human cells: new perspectives in the control of inflammation.

Background: Innate immune responses against infectious agents can act as triggers of inflammatory diseases. On the other hand, various pathogens have developed mechanisms for the evasion of the immune response, based on an inhibition of innate immunity and inflammatory responses. Inflammatory diseases could thus be controlled through the administration of pathogens or pathogen-derived molecules, capable of interfering with the mechanisms at the basis of inflammation. In this framework, the NLRP3 inflammasome is an important component in innate antimicrobial responses and a major player in the inflammatory disease. Parasites of the genus Leishmania are master manipulators of innate immune mechanisms, and different species have been shown to inhibit inflammasome formation. However, the exploitation of pathogenic Leishmania species as blockers of NLRP3-based inflammatory diseases poses safety concerns. Methods: To circumvent safety issues associated with pathogenic parasites, we focused on Leishmania tarentolae, a species of Leishmania that is not infectious to humans. Because NLRP3 typically develops in macrophages, in response to the detection and engulfment microorganisms, we performed our experiments on a monocyte-macrophage cell line (THP-1), either wild type or knockout for ASC, a key component of NLRP3 formation, with determination of cytokines and other markers of inflammation. Results: L. tarentolae was shown to possess the capability of dampening the formation of NLRP3 inflammasome and the consequent expression of pro-inflammatory molecules, with minor differences compared to effects of pathogenic Leishmania species. Conclusion: The non-pathogenic L. tarentolae appears a promising pro-biotic microbe with anti-inflammatory properties or a source of immune modulating cellular fractions or molecules, capable of interfering with the formation of the NLRP3 inflammasome.

Glibenclamide-Loaded Engineered Nanovectors (GNVs) Modulate Autophagy and NLRP3-Inflammasome Activation.

Activation of the NLRP3 inflammasome in response to either exogenous (PAMPs) or endogenous (DAMPs) stimuli results in the production of IL-18, caspase-1 and IL-1ß. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status plays a role in human pathologies, including Alzheimer's disease (AD). Autophagic removal of NLRP3 inflammasome activators can reduce inflammasome activation and inflammation. Likewise, inflammasome signaling pathways regulate autophagy, allowing the development of inflammatory responses but preventing excessive and detrimental inflammation. Nanotechnology led to the development of liposome engineered nanovectors (NVs) that can load and carry drugs. We verified in an in vitro model of AD-associated inflammation the ability of Glibenclamide-loaded NVs (GNVs) to modulate the balance between inflammasome activation and autophagy. Human THP1dM cells were LPS-primed and oligomeric Aß-stimulated in the presence/absence of GNVs. IL-1ß, IL-18 and activated caspase-1 production was evaluated by the Automated Immunoassay System (ELLA); ASC speck formation (a marker of NLRP3 activation) was analyzed by FlowSight Imaging flow-cytometer (AMNIS); the expression of autophagy targets was investigated by RT-PCR and Western blot (WB); and the modulation of autophagy-related up-stream signaling pathways and Tau phosphorylation were WB-quantified. Results showed that GNVs reduce activation of the NLRP3 inflammasome and prevent the Aß-induced phosphorylation of ERK, AKT, and p70S6 kinases, potentiating autophagic flux and counteracting Tau phosphorylation. These preliminary results support the investigation of GNVs as a possible novel strategy in disease and rehabilitation to reduce inflammasome-associated inflammation.

Glibenclamide-Loaded Nanoparticles Reduce NLRP3 Inflammasome Activation and Modulate miR-223-3p/miR-7-1-5p Expression in THP-1 Cells.

The anti-hyperglycemic drug glibenclamide (Glb) might represent an interesting therapeutic option in human neurodegenerative diseases because of its anti-inflammatory activity and its ability to downregulate activation of the NLRP3 inflammasome. Bi-functionalized liposomes that can cross the blood-brain barrier (BBB) may be used to release Glb into the central nervous system (CNS), overcoming its poor solubility and bioavailability. Here, we analyzed in vitro the effect of Glb-loaded nanovectors (GNVs) and Glb itself on NLRP3 inflammasome activation using a lipopolysaccharide- and nigericine-activated THP-1 cell model. Apoptosis-associated speck-like protein containing a CARD (ASC) aggregation and NLRP3-related cytokine (IL-1ß, caspase 1, and IL-18) production and gene expression, as well as the concentration of miR-223-3p and miR-7-1-5p, known to modulate the NLRP3 inflammasome, were evaluated in all conditions. Results showed that both GNVs and Glb reduced significantly ASC-speck oligomerization, transcription and translation of NLRP3, as well as the secretion of caspase 1 and IL-1ß (p < 0.05 for all). Unexpectedly, GNVs/Glb significantly suppressed miR-223-3p and upregulated miR-7-1-5p expression (p < 0.01). These preliminary results thus suggest that GNVs, similarly to Glb, are able to dampen NLRP3 inflammasome activation, inflammatory cytokine release, and modulate miR-223-3p/miR-7-1-5p. Although the mechanisms underlying the complex relation among these elements remain to be further investigated, these results can open new roads to the use of GNVs as a novel strategy to reduce inflammasome activation in disease and rehabilitation.

Alterations of natural killer cells activatory molecules phenotype and function in mothers of ASD children: a pilot study.

Introduction: Autism spectrum disorder (ASD) is accompanied by complex immune alterations and inflammation, and the possible role played by Natural Killer (NK) in such alterations is only barely understood. Methods: To address this question we analysed activating and inhibitory NK receptors, as well as NK cells phenotype and function in a group of mothers of children who developed ASD (ASD-MO; N=24) comparing results to those obtained in mothers of healthy children who did not develop (HC-MO; N=25). Results: Results showed that in ASD-MO compared to HC-MO: 1) NK cells expressing the inhibitory receptor ILT2 are significantly decreased; 2) the activating HLA-G14bp+ polymorphism is more frequently observed and is correlated with the decrease of ILT2-expressing cells; 3) the CD56bright and CD56dim NK subsets are increased; 4) IFNγ and TNF production is reduced; and 5) perforin- and granzymes-releasing NK cells are increased even in unstimulated conditions and could not be upregulated by mitogenic stimulation. Discussion: Results herein reinforce the hypothesis that ASD relatives present traits similar to, but not as severe as the defining features of ASD (Autism endophenotype) and identify a role for NK cells impairment in generating the inflammatory milieu that is observed in ASD.

SARS-CoV-2 ORF3c impairs mitochondrial respiratory metabolism, oxidative stress, and autophagic flux.

Coronaviruses encode a variable number of accessory proteins that are involved in host-virus interaction, suppression of immune responses, or immune evasion. SARS-CoV-2 encodes at least twelve accessory proteins, whose roles during infection have been studied. Nevertheless, the role of the ORF3c accessory protein, an alternative open reading frame of ORF3a, has remained elusive. Herein, we show that the ORF3c protein has a mitochondrial localization and alters mitochondrial metabolism, inducing a shift from glucose to fatty acids oxidation and enhanced oxidative phosphorylation. These effects result in increased ROS production and block of the autophagic flux. In particular, ORF3c affects lysosomal acidification, blocking the normal autophagic degradation process and leading to autolysosome accumulation. We also observed different effect on autophagy for SARS-CoV-2 and batCoV RaTG13 ORF3c proteins; the 36R and 40K sites are necessary and sufficient to determine these effects.

TREM2 Expression and Amyloid-Beta Phagocytosis in Alzheimer's Disease.

Alzheimer's Disease is the most common form of dementia; its key pathological findings include the deposition of extracellular-neurotoxic-plaques composed of amyloid-beta (Ab). AD-pathogenesis involves mechanisms that operate outside the brain, and new researches indicate that peripheral inflammation is an early event in the disease. Herein, we focus on a receptor known as triggering-receptor-expressed-on-myeloid-cells2 (TREM2), which promotes the optimal immune cells function required to attenuate AD-progression and is, therefore, a potential target as peripheral diagnostic and prognostic-biomarker for Alzheimer's Disease. The objective of this exploratory study was to analyze: (1) soluble-TREM2 (sTREM2) plasma and cerebrospinal fluid concentration, (2) TREM2-mRNA, (3) the percentage of TREM2-expressing monocytes, and (4) the concentration of miR-146a-5p and miR-34a-5p suspected to influence TREM2 transcription. Experiments were performed on PBMC collected by 15AD patients and 12age-matched healthy controls that were unstimulated or treated in inflammatory (LPS) conditions and Ab42 for 24 h; Aß42-phagocytosis was also analyzed by AMNIS FlowSight. Results although preliminary, due to limitations by the small sample-size, showed that in AD compared to HC: TREM2 expressing monocytes were reduced, plasma sTREM2 concentration and TREM2-mRNA were significantly upregulated and Ab42-phagocytosis was diminished (for all p < 0.05). miR-34a-5p expression was reduced (p = 0.02) as well in PBMC of AD, and miR-146 was only observed in AD cells (p = 0.0001).

Innate immune responses to three doses of the BNT162b2 mRNA SARS-CoV-2 vaccine.

To explore the effects of SARS-CoV-2-mRNA vaccines on innate immune responses we enrolled 58 individuals who received 3 doses of the BNT162b2 vaccine in a longitudinal study; 45 of these individuals had never been SARS-CoV-2 infected. Results showed that vaccination significantly increased: 1) classical and intermediate inflammatory monocytes, 2) CD56bright, CD56dim, and CD56dim/CD16dim NK cells, and 3) IFN-γ+ ;production as well as perforin and granzyme content by NK cells. Vaccination also reduced expression of the NK inhibitory receptor ILT-2, increasing that of the stimulatory molecule 2DS2. These effects were long-lasting and were boosted by every vaccine dose. Notably, ILT-2 expressing NK cells were reduced even more robustly in COVID-19-recovereed vaccines. BNT162b1 mRNA vaccine is known to induce potent adaptive immune responses; results herein show its ability to modulate innate immune responses as well, offering further support to the indication to proceed with worldwide vaccination efforts to end the SARS-CoV-2 pandemic.

Modulation of Neuroendocrine and Immunological Biomarkers Following Rehabilitation in Sarcopenic Patients.

This study aimed to investigate if rehabilitation could down-regulated sarcopenia-associated inflammation by modulating the crosstalk between the neuroendocrine and immune systems, with the aim of ameliorating quality of life of sarcopenic subjects. A total of 60 sarcopenic patients (49 females and 11 males; median age 74.5, interquartile range 71-79), undergoing a personalized rehabilitation program, have been recruited and subjected to: (1) functional and physical evaluation (Short Physical Performance Battery (SPPB), Barthel Index and Tinetti Test); (2) pro-inflammatory IL-1ß, TNF-α, IL-6, IL-18, and anti-inflammatory IL-10 cytokines plasmatic level measures; and (3) norepinephrine, epinephrine, dopamine, and serotonin neurotransmitter level evaluation at time of enrollment (T0) and once rehabilitation was concluded (1 month, T1). Rehabilitation combined a balance and strength training program with two daily sessions that were fine-tuned and personalized according to the ability of the patient. The results showed a significant increase at T1 in the plasmatic levels of IL-10 (p = 0.018) and of norepinephrine (p = 0.016)), whereas the concentration of IL-18 was significantly reduced (p = 0.012). Notably, changes in norepinephrine were positively correlated with clinical improvements (Tinetti and Barthel scores, p ≤ 0.0001; SPPB scores, p = 0.0002). These results show that efficient rehabilitation induces a reduction of inflammation, suggesting that this effect could be mediated by a modulation of the neuro-immune axis that results in an increase of norepinephrine.

Modulation of MAPK- and PI3/AKT-Dependent Autophagy Signaling by Stavudine (D4T) in PBMC of Alzheimer's Disease Patients.

BACKGROUND: Aß42 deposition plays a pivotal role in AD pathogenesis by inducing the activation of microglial cells and neuroinflammation. This process is antagonized by microglia-mediated clearance of Aß plaques. Activation of the NLRP3 inflammasome is involved in neuroinflammation and in the impairments of Aß-plaque clearance. On the other hand, stavudine (D4T) downregulates the NLRP3 inflammasome and stimulates autophagy-mediated Aß-clearing in a THP-1-derived macrophages. METHODS: We explored the effect of D4T on Aß autophagy in PBMC from AD patients that were primed with LPS and stimulated with Aß oligomers in the absence/presence of D4T. We analyzed the NLRP3 activity by measuring NLRP3-ASC complex formation by AMNIS FlowSight and pro-inflammatory cytokine (IL-1ß, IL-18 and Caspase-1) production by ELISA. The phosphorylation status of p38, ERK, AKT, p70, and the protein expression of CREB, LAMP2A, beclin-1, Caspase-3 and Bcl2 were analyzed by Western blot. RESULTS: Data showed that D4T: (1) downregulates NLRP3 inflammasome activation and the production of down-stream pro-inflammatory cytokines in PBMC; (2) stimulates the phosphorylation of AKT, ERK and p70 as well as LAMP2A, beclin-1 and Bcl2 expression and reduces Caspase-3 expression, suggesting an effect of this compound on autophagy; (3) increases phospho-CREB, which is a downstream target of p-ERK and p-AKT, inducing anti-inflammatory cytokine production and resulting in a possible decrease of Aß-mediated cytotoxicity; and (4) reduces the phosphorylation of p38, a protein involved in the production of pro-inflammatory cytokines and tau hyperphosphorylation. CONCLUSIONS: D4T reduces the activation of the NLRP3 inflammasome, and it might stimulate autophagy as well as the molecular mechanism that modulates Aß cytotoxicity, and D4T might reduce inflammation in the cells of AD patients. It could be very interesting to check the possible beneficial effects of D4T in the clinical scenario.

Simplexviruses Successfully Adapt to Their Host by Fine-Tuning Immune Responses.

Primate herpes simplex viruses are species-specific and relatively harmless to their natural hosts. However, cross-species transmission is often associated with severe disease, as exemplified by the virulence of macacine herpesvirus 1 (B virus) in humans. We performed a genome-wide scan for signals of adaptation of simplexviruses to their hominin hosts. Among core genes, we found evidence of episodic positive selection in three glycoproteins, with several selected sites located in antigenic determinants. Positively selected noncore genes were found to be involved in different immune-escape mechanisms. The herpes simplex virus (HSV)-1/HSV-2 encoded product (ICP47) of one of these genes is known to down-modulate major histocompatibility complex class I expression. This feature is not shared with B virus, which instead up-regulates Human Leukocyte Antigen (HLA)-G, an immunomodulatory molecule. By in vitro expression of different ICP47 mutants, we functionally characterized the selection signals. Results indicated that the selected sites do not represent the sole determinants of binding to the transporter associated with antigen processing (TAP). Conversely, the amino acid status at these sites was sufficient to determine HLA-G up-regulation. In fact, both HSV-1 and HSV-2 ICP47 induced HLA-G when mutated to recapitulate residues in B virus, whereas the mutated version of B virus ICP47 failed to determine HLA-G expression. These differences might contribute to the severity of B virus infection in humans. Importantly, they indicate that the evolution of ICP47 in HSV-1/HSV-2 led to the loss of an immunosuppressive effect. Thus, related simplexviruses finely tune the balance between immunosuppressive and immunostimulatory pathways to promote successful co-existence with their primate hosts.

Increased Levels of Beta-Endorphin and Noradrenaline after a Brief High-Impact Multidimensional Rehabilitation Program in Multiple Sclerosis.

Finding new solutions for the management of multiple sclerosis (MS) is crucial: further research is needed to study the effect of non-pharmacological interventions on the symptoms and the course of the disease, especially on lifestyle. Benefits from a proper lifestyle are evident not only on a clinical level but also on immune and neuro-endocrine systems. A brief high-impact multidimensional rehabilitation program (b-HIPE) was proposed for a sample of people with MS (pwMS) with a medium level of disease disability. We tested the change on clinical parameters and quality of life (QoL) after participation in B-HIPE. We furthermore decided to measure beta-endorphin and catecholamines concentrations pre- and post-participation in the b-HIPE program, due to the relationship between these hormones and the immune system in neurodegenerative diseases. Our results showed that after the b-HIPE program, an improvement of clinical parameters and QoL occurred. Moreover, we found higher levels of beta-endorphin and noradrenaline after participation in the program. These findings highlight the importance of implementing lifestyle interventions in the clinical management of MS. Furthermore, we hypothesize that the B-HIPE program increased beta-endorphin and noradrenaline levels, helping to reduce the inflammation related to MS disease.

Pregnant Women Develop a Specific Immunological Long-Lived Memory Against SARS-COV-2.

It is well established that pregnancy induces deep changes in the immune system. This is part of the physiological adaptation of the female organism to the pregnancy and the immunological tolerance toward the fetus. Indeed, over the three trimesters, the suppressive T regulatory lymphocytes are progressively more represented, while the expression of co-stimulatory molecules decreases overtime. Such adaptations relate to an increased risk of infections and progression to severe disease in pregnant women, potentially resulting in an altered generation of long-lived specific immunological memory of infection contracted during pregnancy. How potent is the immune response against SARS-CoV-2 in infected pregnant women and how long the specific SARS-CoV-2 immunity might last need to be urgently addressed, especially considering the current vaccinal campaign. To address these questions, we analyzed the long-term immunological response upon SARS-CoV-2 infection in pregnant women from delivery to a six-months follow-up. In particular, we investigated the specific antibody production, T cell memory subsets, and inflammation profile. Results show that 80% developed an anti-SARS-CoV-2-specific IgG response, comparable with the general population. While IgG were present only in 50% of the asymptomatic subjects, the antibody production was elicited by infection in all the mild-to-critical patients. The specific T-cell memory subsets rebalanced over-time, and the pro-inflammatory profile triggered by specific SARS-CoV-2 stimulation faded away. These results shed light on SARS-CoV-2-specific immunity in pregnant women; understanding the immunological dynamics of the immune system in response to SARS-CoV-2 is essential for defining proper obstetric management of pregnant women and fine tune gender-specific vaccinal plans.

Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer's Disease.

Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1ß. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pathologies including Alzheimer's Disease (AD). MicroRNAs (miR-NAs) target the 3'UTR region of NLRP3, preventing the activation of the inflammasome and inhibiting cytokine production. Because Stavudine (D4T), an antiretroviral drug, was recently shown to reduce inflammasome activation, we verified whether its effect is mediated by miR-7-5p, miR-22-3p, miR-30e-5p and miR-223-3p: miRNAs that bind the NLRP3-mRNA-UTR region and interfere with protein translation, reducing NLRP3 activation. Peripheral blood mononuclear cells (PBMCs) of twenty AD patients and ten sex-matched Healthy Controls (HC) were stimulated with Lipopolysaccharides (LPS)+Amyloid-beta (Aß42) in the absence/presence of D4T. Expression of genes within the inflammasome complex and of miRNAs was evaluated by RT-PCR; cytokines and caspase-1 production was measured by ELISA. Results have shown that: NLRP3, ASC, IL-1ß and IL-18 expression, as well as IL-18, IL-1ß and caspase-1 production, were significantly augmented (p < 0.05) in LPS+Aß42-stimulated PBMCs of AD patients compared to HC. D4T reduced the expression of inflammasome genes and cytokine production (p < 0.005). miR-7-5p and miR-223-3p expression was significantly increased in LPS+Aß42-stimulated PBMCs of AD patients (p < 0.05), and it was reduced by D4T in AD alone. In conclusion: miR-223-3p and mir-7-5p expression is increased in AD, but this does not result in down-regulation of NLRP3 inflammasome expression and of IL-1ß and IL-18 production. D4T increased miRNA expression in HC but had an opposite effect in AD, suggesting that miRNA regulatory mechanisms are altered in AD.

NK Cell Subpopulations and Receptor Expression in Recovering SARS-CoV-2 Infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic of coronavirus disease (COVID-19). Whereas in most cases COVID-19 is asymptomatic or pauci-symptomatic, extremely severe clinical forms are observed. In this case, complex immune dysregulations and an excessive inflammatory response are reported and are the main cause of morbidity and mortality. Natural killer cells are key players in the control of viral infection, and their activity is regulated by a tight balance between activating and inhibitory receptors; an alteration of NK activity was suggested to be associated with the development of severe forms of COVID-19. In this study, we analyzed peripheral NK cell subpopulations and the expression of activating and inhibitory receptors in 30 patients suffering from neurological conditions who recovered from mild, moderate, or severe SARS-CoV-2 infection, comparing the results to those of 10 SARS-CoV-2-uninfected patients. Results showed that an expansion of NK subset with lower cytolytic activity and an augmented expression of the 2DL1 inhibitory receptor, particularly when in association with the C2 ligand (KIR2DL1-C2), characterized the immunological scenario of severe COVID-19 infection. An increase of NK expressing the ILT2 inhibitory receptor was instead seen in patients recovering from mild or moderate infection compared to controls. Results herein suggest that the KIR2DL1-C2 NK inhibitory complex is a risk factor toward the development of severe form of COVID-19. Our results confirm that a complex alteration of NK activity is present in COVID-19 infection and offer a molecular explanation for this observation.

Influence of a High-Impact Multidimensional Rehabilitation Program on the Gut Microbiota of Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high-impact multidimensional rehabilitation program (B-HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B-HIPE resulted in modulation of the MS-typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short-chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro-inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients' quality of life.

Inflammatory Responses to Monomeric and Aggregated α-Synuclein in Peripheral Blood of Parkinson Disease Patients.

To investigate whether different forms of α-synuclein (α-syn) proteins can induce inflammation and activate the NLRP3 inflammasome, we stimulated with monomeric or aggregated α-syn peripheral blood mononuclear cells of Parkinson disease (PD) patients and age- and sex-matched healthy controls (HC). ASC-speck formation, i.e., the intracellular generation of functionally active inflammasome complexes, as well as the production of inflammasome-related [caspase-1, interleukin 1ß (IL-18), and IL-1ß], and pro-IL-6, or anti-IL-10 inflammatory cytokines were evaluated. Gastrointestinal permeability, suggested to be altered in PD, was also investigated by measuring plasma concentration of lipopolysaccharide (LPS) and I-FABP (fatty acid-binding protein). ASC-speck expression, as well as IL-18 and caspase-1 production and LPS and I-FABP plasma concentration, was comparable in PD and HC, indicating that α-syn does not stimulate the NLRP3 inflammasome and that PD does not associate with alterations of intestinal permeability. Interestingly, though, IL-1ß and IL-6 production was increased, whereas that of IL-10 was reduced in α-syn-stimulated cells of PD compared to HC, suggesting that PD-associated neuroinflammation is not the consequence of the activation of the NLRP3 inflammasome but rather of an imbalance between proinflammatory and anti-inflammatory cytokines.

Deregulation of IL-37 and its miRNAs modulators in sarcopenic patients after rehabilitation.

BACKGROUND: sarcopenia is a highly prevalent condition in elderly individuals which is characterized by loss of muscle mass and functions; recent results showed that it is also associated with inflammation. Rehabilitation protocols for sarcopenia are designed to improve physical conditions, but very scarce data are available on their effects on inflammation We verified whether in sarcopenic patients the inflammation is reduced by rehabilitation and investigated the biological correlates of such effect. METHODS: Twenty-one sarcopenic patients undergoing a specifically-designed rehabilitation program were enrolled in the study. Physical, cognitive and nutritional parameters, as well as the concentration of C-Reactive Protein (CRP), pro-and anti-inflammatory cytokines and cytokine production-modulating miRNAs were measured at the beginning (T0) and at end (30-days; T1) of the rehabilitation. RESULTS: Rehabilitation resulted in a significant improvement of physical and cognitive conditions; this was accompanied by a significant reduction of CRP (p = 0.04) as well as of IL-18 (p = 0.008) and IL-37 (p = 0.009) concentration. Notably, the concentration of miR-335-3p (p = 0.007) and miR-657, the two known post-transcriptional regulators of IL-37 production, was increased by the rehabilitation protocol. CONCLUSIONS: Results herein confirm that successful rehabilitation for sarcopenia results in a reduction of the inflammatory milieu, raise the possibility that IL-37 may be a key target to monitor the rehabilitation-associated improvement in sarcopenia, and suggest that this cytokine could be a therapeutic target in sarcopenic patients.

The Role of the Inflammasome in Neurodegenerative Diseases.

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.

ERAPs Reduce In Vitro HIV Infection by Activating Innate Immune Response.

Recombinant human (rh) ERAP2-treated PBMCs are less susceptible to in vitro HIV-1 infection even when CD8+ T cells are depleted. We therefore investigated whether ERAP2 can trigger other immunocompetent cells, boosting their antiviral potential. To this end, human monocyte-derived macrophages (MDMs) differentiated from PBMCs of 15 healthy donors were in vitro HIV-1 infected in the presence/absence of 100 ng/ml of rhERAP2, rhERAP1, or rhERAP1+rhERAP2. Notably, rhERAP2 treatment resulted in a 7-fold reduction of HIV-1 replication in MDMs (p < 0.05). This antiviral activity was associated with an increased mRNA expression of CD80, IL-1ß, IL-18, and TNF-α (p < 0.01 for cytokine) in in vitro ERAP2-treated HIV-1-infected MDMs and a greater release of IL-1ß, TNF-α, IL-6, and IL-8 (p < 0.01 for each cytokine). The rhERAPs addition also induced the functional inflammasome activation by ASC speck formation in monocytes (p < 0.01) and in THP1-derived macrophages (p < 0.01) as well as a rise in the percentage of activated classical (CD14+CD16-HLA-DRII+CCR7+) and intermediate (CD14++CD16+HLA-DRII+CCR7+) monocytes (p < 0.02). Finally, THP-1-derived macrophages showed an increased phagocytosis following all ERAPs treatments. The discovery that ERAPs are able to trigger several antiviral mechanisms in monocyte/macrophages suggests that their anti-HIV potential is not limited to their canonical role in Ag presentation and CD8+ T cell activation. These findings pose the premise to further investigate the role of ERAPs in both innate and adaptive immunostimulatory pathways and suggest their potential use in novel preventive and therapeutic approaches against HIV-1 infection.

Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift.

The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called 'First 1000 Days') are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.