Papers by valentina pucino
International Journal of Molecular Sciences, Mar 21, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
International Journal of Molecular Sciences
Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate ne... more Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and n...
Frontiers in Immunology
IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). ... more IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters.MethodsSynovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using tr...
doi: 10.3389/fimmu.2014.00143 Neuro-endocrine networks controlling immune system in health and di... more doi: 10.3389/fimmu.2014.00143 Neuro-endocrine networks controlling immune system in health and disease
Clinical and experimental immunology, Jan 12, 2016
Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. A... more Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR) and interleukin 6 (IL-6) and SAA serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimes. Serum concentrations of sTNFR (p=0.008), leptin (p=0.0011), sCD40L (<0.0001), and IL-6...
Metabolism, 2015
Context. Anorexia nervosa (AN) is an excessive form of calorie restriction (CR) associated with p... more Context. Anorexia nervosa (AN) is an excessive form of calorie restriction (CR) associated with pathological weight loss and alterations of the immune system. However, AN patients seem to be protected from common viral infections. Objectives. To investigate the metabolic and molecular adaptations induced by sustained extreme CR in the peripheral blood mononuclear cells (PBMCs) of patients with restrictive alimentary AN. Design. Inflammatory cytokines and adipokines were measured in 15 young (age range, 15-24 years) AN female patients and 20 age-matched healthy controls. Isolated PBMCs were immunophenotyped by flow cytometry, and glycolysis and mitochondrial respiration were determined by measuring the extracellular acidification and oxygen consumption rate. Stress resistance to H 2 O 2 and the antioxidant transcriptional profile of PBMCs and human fibroblasts incubated with sera from AN patients were also determined.
Metabolism, 2015
Over the last few years, a series of molecules known to play a function in metabolism have also b... more Over the last few years, a series of molecules known to play a function in metabolism have also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response both in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of pro-inflammatory pathogenic cytokines. In this context, leptin could represent the "missing link" between immune response, metabolic function, and nutritional status. Strategies aimed at interfering with the leptin axis could represent innovative therapeutic tools for infections and autoimmune disorders. This chapter reviews the most recent advances in the role of leptin in autoimmune responses.
Leptin, 2014
The past 20 years of research on leptin have provided crucial information on the link between met... more The past 20 years of research on leptin have provided crucial information on the link between metabolic state and immune system function. Adipocytes influence not only the endocrine system but also the immune response, through several cytokine-like mediators known as adipokines, which include leptin. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, or degenerative disease including autoimmunity and cancer. We discuss here the role of leptin in the regulation the immune response, innate and adaptive response, both in normal and pathological conditions and the influence of this cytokine/hormone in the physiopathology of inflammation.
Journal of Leukocyte Biology, 2015
TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mu... more TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4(+)CD25(-) and regulatory CD4(+)CD25(+) T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4(+) conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.
Clinical and experimental rheumatology, 2017
Poster Presentations
develop particularly severe bone fragility accompanied with high risk factors for fragility fract... more develop particularly severe bone fragility accompanied with high risk factors for fragility fractures 1,2. Although bisphosphonate is recommended for treatment of osteoporosis related RA and glucocorticoid-induced-osteoporosis 3 , there are more frequently fractures than expected from bone mineral density based prediction even after used bisphosphonate. Objectives: To clarify the pathological mechanisms of bone fragility of these RA patients, we investigated bone biopsy samples obtained from RA and normal postmenopausal patients. Methods: We examined 10 female postmenopausal RA patients receiving glucocorticoid and bisphosphonate therapy (RA group) and 10 age-matched female patients with postmenopausal osteoporosis (Ctl group) selected from patients who required autologous iliac bone grafts. Analyses of clinical data, bone mineral density, serum metabolic markers, bone quality and material mechanical property of biopsy sample were performed. Results: Although bone mineral density didn't show significant differences, RA group had significantly higher score of fracture risk assessment tool (FRAX), number and severity of existing vertebral fractures. Control RA p FRAX score (%) Major osteoporosis fx. 10.7±4.8 33.4±8.0 <0.001 Femoral neck fx. 2.8±2.4 9.9±6.1 0.002 Clinical fragility fx. Number 4 16 Severity (# x grade) 4 29 Mechanical strength (N/mm) 218.8±24.6 164.9±36.5 0.001 RA group exhibited significant bone quality abnormalities including deterioration of the bone microstructure, decreased calcification of the bone matrix, increased osteocyte atrophy and empty lacunae (Figure), and an impairment bone material strength properties. Conclusions: Our findings showed that RA patients receiving glucocorticoid treatment have severe bone fragility regardless of increased bone quantity by using bisphosphonate. The functional deteriorations of the osteocyte system and the abnormalities of bone quality might induce bone fragility fracture. Therefore, management of osteoporosis associated with RA should be targeted about bone quality as well as bone quantity. References: [1] Kanis JA et al.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (C... more Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells. Animal modeling has been critical for addressing MS pathogenesis. The three most characterized animal models of MS are (1) the experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally-induced chronic demyelinating disease, known as Theiler׳s murine encephalomyelitis virus (TMEV) infection and (3) the toxin-induced demyelination. All these models, in a complementary way, have allowed to reach a good knowledge of the pathogenesis of MS. Specifically, EAE is the model which better reflects the autoimmune pathogenesis of MS and is extremely useful to study potential experimental treatments. Furthermore, both TMEV and toxin-induced demyelination models are suitable for characterizing the role of the axonal injury/repair and the remyelination process in MS. In conclusion, animal models, despite their limitations, remain the most useful instrument for implementing the study of MS.
Frontiers in Immunology
Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and or... more Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggest...
Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited aut... more Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited auto-inflammatory disorder caused by mutations in TNFRSF1A, the gene encoding for tumour necrosis factor receptor superfamily 1A. The mechanism of inflammation in TRAPS is still unknown. In particular the involvement of adaptive immunity in autoinflammatory disorders hasn’t been investigated yet. In this project we investigated how TNFa/TNRSF1A signalling network regulates T cell responses. In particular, we focused on conventional CD4+CD25- (Tconv) and regulatory CD4+CD25+ (Treg) T cell functions in TRAPS patients carrying either high or low penetrance mutation in TNFRSF1A gene (HP-TRAPS and LP-TRAPS, respectively). HP-TRAPS showed an upregulation of several inflammation-related molecular signalling pathways in Tconv cells. In addition, these patients had a lower frequency of peripheral Treg cells which also displayed a defective suppressive phenotype. These alterations were partially foun...
Several studies have highlighted the interplay between metabolism, immunity and inflammation. Bot... more Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipocytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.
Annals of the Rheumatic Diseases
Background Behçet's disease (BD) is a rare and poorly understood condition characterised by s... more Background Behçet's disease (BD) is a rare and poorly understood condition characterised by systemic inflammation. Current biomarkers are still largely insensitive and unable to predict disease progression and response to treatment in BD patients. Objectives The specific aims of this study were i) to explore serum levels of soluble CD40L (sCD40L), soluble intracellular-adhesion-molecule (sICAM-1), monocyte-chemoattractant-protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble-type 1 tumour-necrosis-factor-receptor (sTNFR), interleukin-6 (IL-6) and serum-amyloid-A (SAA); ii) to evaluate potential correlations between the putative circulating biomarkers with the demographic profile, disease activity, organ involvement, genetical background, and different therapeutic regimes. Methods 57 serum samples were collected from 27 BD patients and 35 healthy controls (HC) after written consent. Demographic and clinical data are summarized in Table 1. Adipocytokines were analyzed using the bead-based-analyte-detection-system. Data were acquired by flow-cytometry. SAA serum concentration was determined with a enzyme linked-immunosorbent assay (ELISA). We used ANOVA test to identify statistical differences. P<0.05 was considered statistically significant. Results BD patients showed higher levels of circulating sTNFR (p=0.008), leptin (p=0.0011), sCD40L (<0.0001), and IL-6 (p=0.0154) than HC while no difference was found in MCP-1, MPO, sICAM, and resistin serum levels. Patients HLA-B51- had higher sTNFR and sICAM-1 serum levels than HC (p=0.0034, p=0.0037, respectively), while sICAM levels were significantly higher in patients HLA-B51- than in patients HLAB51+ (p=0.0010) as well as leptin was significantly higher in both HLA-B51+ and HLA-B51- BD patients than in HC (p=0.0183, p=0.0303, respectively). Patients treated with biologic-agents showed significantly higher sTNFR and leptin serum levels when compared to DMARDs-treated-patients (p=0.0246,p=0.0023, respectively). Moreover, sTNFR was found higher in patients with inactive disease and in patients over 40 years than HC (p=0.0104, p=0.0329, respectively).Table 1. Demographic and clinical data of BD patients BD patients BD serum samples Males/females 12/15 27/30 Age (mean ± SD), years 45.7±13.54 51.19±30.26 Disease onset (mean ± SD), years 32.55±14.35 34.15±13.48 Disease duration (mean ± SD), years 13.59±12.67 13.85±12.34 HLA-B51 positivity. n (%) 17 (62.96) 40 (70.17) Oral/genital aphtosis 23 (85.18) 39 (68.42) Skin manifestations 10 (37.03) 12 (21.05) Uveitis 11 (40.74) 20 (35.08) SNC involvement 18 (66.66) 26 (45.61) Vascular involvement 2 (7.40) 4 (07.01) Gastrointestinal manifestations 4 (14.81) 4 (07.01) Musculoskeletal involvement 20 (74.07) 27 (47.36) Conclusions The identification of a specific meta-immunological profile associated with disease status and response to therapy may contribute to our understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach. Disclosure of Interest None declared
Metabolism, 2014
In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)... more In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)CD25(-) conventional (Tconv) T cells. In vitro treatment with recombinant human leptin determined an inhibition of autophagy during T cell receptor (TCR) stimulation, and this phenomenon was dose- and time-dependent. The events were secondary to the activation of the mammalian-target of rapamycin (mTOR)-pathway induced by leptin, as testified by its reversion induced by mTOR inhibition with rapamycin. At molecular level these phenomena associated with Bcl-2 up-regulation and its interaction with Beclin-1, whose complex exerts a negative effect on autophagy. The impact of leptin on autophagy of Tconv cells was determined at biochemical level by western blotting and by flow cytometry; the interaction between BCL-2 and Beclin-1 by co-immunoprecipitation assays. Our results, suggest that in unconditioned, freshly-isolated human Tconv cells, autophagy and proliferation are controlled by leptin during TCR-engagement, and that both phenomena occur alternatively indicating a balance between these processes during immune activation.
Translational Autoimmunity
Frontiers in Immunology, 2014
The nervous and immune systems have long been considered as compartments that perform separate an... more The nervous and immune systems have long been considered as compartments that perform separate and different functions. However, recent clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders, such as multiple sclerosis (MS), might involve factors, hormones, and neural mediators that link the immune and nervous system. These molecules are members of the same superfamily, which allow the mutual and bi-directional neural-immune interaction. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones that control food intake and metabolism, has suggested that nutritional/metabolic status, acting at central level, can control immune self-tolerance, since it promotes experimental autoimmune encephalomyelitis, an animal model of MS. Here, we summarize the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. Understanding this coordinated interaction may pave the way for novel therapeutic approaches to increase host defense and suppress immune-mediated disorders.
Nature Reviews Immunology
The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the m... more The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.
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Papers by valentina pucino