Publications by authors named "Giuseppe Matarese"

183 Publications

A novel smaller β-defensin-derived peptide is active against multidrug-resistant bacterial strains.

FASEB J 2021 12;35(12):e22026

Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.

Antibiotic resistance is becoming a severe obstacle in the fight against acute and chronic infectious diseases that accompany most degenerative illnesses from neoplasia to osteo-arthritis and obesity. Currently, the race is on to identify pharmaceutical molecules or combinations of molecules able to prevent or reduce the insurgence and/or progression of infectivity. Attempts to substitute antibiotics with antimicrobial peptides have, thus far, met with little success against multidrug-resistant (MDR) bacterial strains. During the last decade, we designed and studied the activity and features of human β-defensin analogs, which are salt-resistant, and hence active also under high salt concentrations as, for instance, in cystic fibrosis. Herein, we describe the design, synthesis, and major features of a new 21 aa long molecule, peptide γ2. The latter derives from the γ-core of the β-defensin natural molecules, a small fragment of these molecules still bearing high antibacterial activity. We found that peptide γ2, which contains only one disulphide bond, recapitulates most of the biological properties of natural human β-defensins and can also counteract both Gram-positive and Gram-negative MDR bacterial strains and biofilm formation. Moreover, it has great stability in human serum thereby enhancing its antibacterial presence and activity without cytotoxicity in human cells. In conclusion, peptide γ2 is a promising new weapon also in the battle against intractable infectious diseases.
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http://dx.doi.org/10.1096/fj.202002330RRDOI Listing
December 2021

CD4 T-Cell Activation Prompts Suppressive Function by Extracellular Vesicle-Associated MicroRNAs.

Front Cell Dev Biol 2021 27;9:753884. Epub 2021 Oct 27.

IRCCS MultiMedica, Milan, Italy.

MicroRNAs (miRNAs), small non-coding molecules targeting messenger RNAs and inhibiting protein translation, modulate key biological processes, including cell growth and development, energy utilization, and homeostasis. In particular, miRNAs control the differentiation, survival, and activation of CD4 T conventional (Tconv) cells, key players of the adaptive immunity, and regulate the physiological response to infections and the pathological loss of immune homeostasis in autoimmunity. Upon T-cell receptor (TCR) stimulation, the described global miRNA quantitative decrease occurring in T cells is believed to promote the acquisition of effector functions by relaxing the post-transcriptional repression of genes associated with proliferation and cell activity. MiRNAs were initially thought to get downregulated uniquely by intracellular degradation; on the other hand, miRNA secretion extracellular vesicles (EVs) represents an additional mechanism of rapid downregulation. By focusing on molecular interactions by means of graph theory, we have found that miRNAs released by TCR-stimulated Tconv cells are significantly enriched for targeting transcripts upregulated upon stimulation, including those encoding for crucial proteins associated with Tconv cell activation and function. Based on this computational approach, we present our perspective based on the following hypothesis: a stimulated Tconv cell will release miRNAs targeting genes associated with the effector function in the extracellular space in association with EVs, which will thus possess a suppressive potential toward other Tconv cells in the paracrine environment. We also propose possible future directions of investigation aimed at taking advantage of these phenomena to control Tconv cell effector function in health and autoimmunity.
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http://dx.doi.org/10.3389/fcell.2021.753884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580371PMC
October 2021

CD8 T cells specific for cryptic apoptosis-associated epitopes exacerbate experimental autoimmune encephalomyelitis.

Cell Death Dis 2021 10 29;12(11):1026. Epub 2021 Oct 29.

Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy.

The autoimmune immunopathology occurring in multiple sclerosis (MS) is sustained by myelin-specific and -nonspecific CD8 T cells. We have previously shown that, in MS, activated T cells undergoing apoptosis induce a CD8 T cell response directed against antigens that are unveiled during the apoptotic process, namely caspase-cleaved structural proteins such as non-muscle myosin and vimentin. Here, we have explored in vivo the development and the function of the immune responses to cryptic apoptosis-associated epitopes (AEs) in a well-established mouse model of MS, experimental autoimmune encephalomyelitis (EAE), through a combination of immunization approaches, multiparametric flow cytometry, and functional assays. First, we confirmed that this model recapitulated the main findings observed in MS patients, namely that apoptotic T cells and effector/memory AE-specific CD8 T cells accumulate in the central nervous system of mice with EAE, positively correlating with disease severity. Interestingly, we found that AE-specific CD8 T cells were present also in the lymphoid organs of unprimed mice, proliferated under peptide stimulation in vitro, but failed to respond to peptide immunization in vivo, suggesting a physiological control of this response. However, when mice were immunized with AEs along with EAE induction, AE-specific CD8 T cells with an effector/memory phenotype accumulated in the central nervous system, and the disease severity was exacerbated. In conclusion, we demonstrate that AE-specific autoimmunity may contribute to immunopathology in neuroinflammation.
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http://dx.doi.org/10.1038/s41419-021-04310-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556378PMC
October 2021

Reimagining an immunological dogma.

Nat Immunol 2021 11;22(11):1355-1358

Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

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http://dx.doi.org/10.1038/s41590-021-01046-5DOI Listing
November 2021

16S rRNA of Mucosal Colon Microbiome and CCL2 Circulating Levels Are Potential Biomarkers in Colorectal Cancer.

Int J Mol Sci 2021 Oct 4;22(19). Epub 2021 Oct 4.

CEINGE Biotecnologie Avanzate S.C.a R.L., 80131 Naples, Italy.

Colorectal cancer (CRC) is one of the most common malignancies in the Western world and intestinal dysbiosis might contribute to its pathogenesis. The mucosal colon microbiome and C-C motif chemokine 2 (CCL2) were investigated in 20 healthy controls (HC) and 20 CRC patients using 16S rRNA sequencing and immunoluminescent assay, respectively. A total of 10 HC subjects were classified as overweight/obese (OW/OB_HC) and 10 subjects were normal weight (NW_HC); 15 CRC patients were classified as OW/OB_CRC and 5 patients were NW_CRC. Results: and were more abundant in OW/OB_HC than in NW_HC microbiomes. Globally, , , , and were significantly increased in CRC patient tumor/lesioned tissue (CRC_LT) and CRC patient unlesioned tissue (CRC_ULT) microbiomes compared to HC microbiomes. CCL2 circulating levels were associated with tumor presence and with the abundance of , and . Our data suggest that mucosal colon dysbiosis might contribute to CRC pathogenesis by inducing inflammation. Notably, , which was more abundant in the OW/OB_HC than in the NW_HC microbiomes, might represent a putative link between obesity and increased CRC risk.
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http://dx.doi.org/10.3390/ijms221910747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509685PMC
October 2021

PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism.

Mol Oncol 2021 Sep 17. Epub 2021 Sep 17.

Department of Biology, University of Rome Tor Vergata, Rome, Italy.

Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1 CD8 T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1 counterparts. Also, PD-1 lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondrial fragmentation following T-cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1 CD8 T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.
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http://dx.doi.org/10.1002/1878-0261.13103DOI Listing
September 2021

MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis.

Neuropathol Appl Neurobiol 2021 Sep 7. Epub 2021 Sep 7.

Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy.

Aim: We recently proposed miR-142-3p as a molecular player in inflammatory synaptopathy, a new pathogenic hallmark of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE), that leads to neuronal loss independently of demyelination. MiR-142-3p seems to be unique among potential biomarker candidates in MS, since it is an inflammatory miRNA playing a dual role in the immune and central nervous systems. Here, we aimed to verify the impact of miR-142-3p circulating in the cerebrospinal fluid (CSF) of MS patients on clinical parameters, neuronal excitability and its potential interaction with disease modifying therapies (DMTs).

Methods And Results: In a cohort of 151 MS patients, we found positive correlations between CSF miR-142-3p levels and clinical progression, IL-1β signalling as well as synaptic excitability measured by transcranial magnetic stimulation. Furthermore, therapy response of patients with 'low miR-142-3p' to dimethyl fumarate (DMF), an established disease-modifying treatment (DMT), was superior to that of patients with 'high miR-142-3p' levels. Accordingly, the EAE clinical course of heterozygous miR-142 mice was ameliorated by peripheral DMF treatment with a greater impact relative to their wild type littermates. In addition, a central protective effect of this drug was observed following intracerebroventricular and ex vivo acute treatments of EAE wild type mice, showing a rescue of miR-142-3p-dependent glutamatergic alterations. By means of electrophysiology, molecular and biochemical analysis, we suggest miR-142-3p as a molecular target of DMF.

Conclusion: MiR-142-3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies.
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http://dx.doi.org/10.1111/nan.12765DOI Listing
September 2021

Effect of time and titer in convalescent plasma therapy for COVID-19.

iScience 2021 Aug 22;24(8):102898. Epub 2021 Jul 22.

Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Naples, Italy.

The clinical benefit of convalescent plasma (CP) for patients with coronavirus disease (COVID)-19 is still debated. In this systematic review and meta-analysis, we selected 10 randomized clinical trials (RCTs) and 15 non-randomized studies (total number of patients = 22,591) of CP treatment and evaluated two different scenarios: (1) disease stage of plasma recipients and (2) donated plasma antibody titer, considering all-cause mortality at the latest follow-up. Our results show that, when provided at early stages of the disease, CP significantly reduced mortality: risk ratio (RR) 0.72 (0.68, 0.77), p < 0.00001, while provided in severe or critical conditions, it did not (RR: 0.94 [0.86, 1.04], p = 0.22). On the other hand, the benefit on mortality was not increased by using plasma with a high-antibody titer compared with unselected plasma. This meta-analysis might promote CP usage in patients with early-stage COVID-19 in further RCTs to maximize its benefit in decreasing mortality, especially in less affluent countries.
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http://dx.doi.org/10.1016/j.isci.2021.102898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297982PMC
August 2021

Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation.

Biology (Basel) 2021 06 30;10(7). Epub 2021 Jun 30.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction.

Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer.

Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca, reduced OCR and ATP synthesis, and elevated ROS production.

Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.
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http://dx.doi.org/10.3390/biology10070609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301075PMC
June 2021

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential.

Immunity 2021 07 17;54(7):1543-1560.e6. Epub 2021 May 17.

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Napoli, Italy. Electronic address:

Human CD4CD25FOXP3 regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.
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http://dx.doi.org/10.1016/j.immuni.2021.04.014DOI Listing
July 2021

Metabolomics, Lipidomics, and Immunometabolism.

Methods Mol Biol 2021 ;2285:319-328

Istituto per l'Endocrinologia e l'Oncologia Sperimentale-Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy.

Metabolomics, lipidomics, and the study of cellular metabolism are gaining increasing interest particularly in the field of immunology, since the activation and effector functions of immune cells are profoundly controlled by changes in cellular metabolic asset. Among the different techniques that can be used for the evaluation of cellular metabolism, the Seahorse Extracellular Flux Analyzer allows the real time measurement of both glycolytic and mitochondrial respiration pathways in cells of interest, through the assessment of extracellular acidification and oxygen consumption rate. Metabolomics, on the other hand, is the high-throughput analysis of metabolites, i.e., the substrates, intermediates, and products of cellular metabolism, starting from biofluids, cells or tissues. The metabolome does not include lipids as their properties are different from water-soluble metabolites and are classified under the lipidome. Lipidomics analysis allows the identification and quantification of lipid species. Metabolomics and lipidomics are currently performed with mass-spectrometry coupled with liquid or gas chromatography (LC-MS or GC-MS) and/or nuclear-magnetic resonance (NMR). Here we describe the protocol for the evaluation of metabolic rate, metabolomics, and lipidomics in T cells, examining the detailed experimental approaches.
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http://dx.doi.org/10.1007/978-1-0716-1311-5_24DOI Listing
June 2021

The pleiotropic roles of leptin in metabolism, immunity, and cancer.

J Exp Med 2021 05;218(5)

Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Naples, Italy.

The discovery of the archetypal adipocytokine leptin and how it regulates energy homeostasis have represented breakthroughs in our understanding of the endocrine function of the adipose tissue and the biological determinants of human obesity. Investigations on leptin have also been instrumental in identifying physio-pathological connections between metabolic regulation and multiple immunological functions. For example, the description of the promoting activities of leptin on inflammation and cell proliferation have recognized the detrimental effects of leptin in connecting dysmetabolic conditions with cancer and with onset and/or progression of autoimmune disease. Here we review the multiple biological functions and complex framework of operations of leptin, discussing why and how the pleiotropic activities of this adipocytokine still pose major hurdles in the development of effective leptin-based therapeutic opportunities for different clinical conditions.
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http://dx.doi.org/10.1084/jem.20191593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056770PMC
May 2021

Estimating asymptomatic SARS-CoV-2 infections in a geographic area of low disease incidence.

BMC Infect Dis 2021 Apr 15;21(1):350. Epub 2021 Apr 15.

Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Via S. Pansini 5, 80131, Naples, Italy.

Background: The SARS-CoV-2 infection has emerged as a rapidly spreading infection. Today it is relatively easy to isolate Covid-19 symptomatic cases, while remains problematic to control the disease spread by infected but symptom-free individuals. The control of this possible path of contagion requires drastic measures of social distancing, which imply the suspension of most activities and generate economic and social issues. This study is aimed at estimating the percentage of asymptomatic SARS-CoV-2 infection in a geographic area with relatively low incidence of Covid-19.

Methods: Blood serum samples from 388 healthy volunteers were analyzed for the presence of anti-SARS-CoV-2 IgG by using an ELISA assay based on recombinant viral nucleocapsid protein.

Results: We found that 7 out of 388 healthy volunteers, who declared no symptoms of Covid-19, like fever, cough, fatigue etc., in the preceding 5 months, have bona fide serum anti-SARS-CoV-2 IgG, that is 1.8% of the asymptomatic population (95% confidence interval: 0.69-2.91%).

Conclusions: The estimated range of asymptomatic individuals with anti-SARS-CoV-2 IgG should be between 26,565 and 112, 350. In the same geographic area, there are 4665 symptomatic diagnosed cases.
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http://dx.doi.org/10.1186/s12879-021-06054-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046491PMC
April 2021

Different Susceptibility of T and B Cells to Cladribine Depends On Their Levels of Deoxycytidine Kinase Activity Linked to Activation Status.

J Neuroimmune Pharmacol 2021 Apr 14. Epub 2021 Apr 14.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (F.C, A.U.), F.I., N.KdeR., A.U.) and Centre of Excellence for Biomedical Research (F.C., A.U.), University of Genova, Genoa, Italy.

Deoxycytidine kinase (dCK) and 5' deoxynucleotidase (NT5C2) are involved in metabolism of cladribine (2CdA), the immunomodulatory drug for multiple sclerosis; by mediating phosphorylation (activation) or phosphorolysis (deactivation) of 2CdA, respectively, these enzymes promote or prevent its accumulation in the cell, which leads to cell death. In particular, lymphocytes which present with a high intracellular dCK/NT5C2 ratio are more sensitive to 2CdA than other immune cells. We aim at determining if the expression of these enzymes and/or their activity differ in specific progenitor and mature immune cells and are influenced by cellular activation and/or exposure to 2CdA. Flow cytometry analysis showed no difference in dCK/NT5C2 ratio in progenitor and mature immune cells. 2CdA induced apoptosis in stimulated T and B cells and unstimulated B cells. dCK expression was enhanced by 2CdA at mRNA and protein levels in activated T cells and mRNA level in activated B cells. dCK activity, measured through an in-house luminescence release enzyme assay was higher in activated T and B cells, and such an increase was abrogated in activated B cells, but not T cells, upon exposure to 2CdA. These results reveal an important relationship between dCK activity and the effect of 2CdA on B and T cells, according to their activation status. Further study is warranted to evaluate whether dCK activity could, in the future, be a suitable predictive biomarker of lymphocyte response to 2CdA.
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http://dx.doi.org/10.1007/s11481-021-09994-3DOI Listing
April 2021

Novel acquisitions in cell immunometabolism.

Mol Aspects Med 2021 02 5;77:100945. Epub 2021 Feb 5.

Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy; Istituto per L'Endocrinologia e L'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), 80131, Napoli, Italy.

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http://dx.doi.org/10.1016/j.mam.2021.100945DOI Listing
February 2021

SARS-CoV-2 meta-interactome suggests disease-specific, autoimmune pathophysiologies and therapeutic targets.

F1000Res 2020 17;9:992. Epub 2020 Aug 17.

Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, 00189, Italy.

Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network's most critical nodes. We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.
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http://dx.doi.org/10.12688/f1000research.25593.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791351PMC
January 2021

Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis.

Cell Metab 2021 02 8;33(2):300-318.e12. Epub 2021 Jan 8.

Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address:

There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB.
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http://dx.doi.org/10.1016/j.cmet.2020.12.016DOI Listing
February 2021

Anti-CD2 Antibody-Coated Nanoparticles Containing IL-2 Induce NK Cells That Protect Lupus Mice a TGF-β-Dependent Mechanism.

Front Immunol 2020 16;11:583338. Epub 2020 Dec 16.

Department of Medicine, University of California Los Angeles, Los Angeles, CA, United States.

We recently reported that the treatment with nanoparticles (NPs) loaded with tolerogenic cytokines suppressed the manifestations of lupus-like disease induced by the transfer of donor CD4 T cells from DBA/2 mice into (C57BL/6 × DBA/2)F (BDF1) mice. Although the protective effects were ascribed to the induction of adaptive CD4 and CD8 T regulatory cells, the results suggested that another population of immune cells could be involved. Here we report that NK cells critically contribute to the protection from lupus-like disease conferred by NPs to BDF1 mice, and that this effect is TGF-β-dependent.
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http://dx.doi.org/10.3389/fimmu.2020.583338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772200PMC
June 2021

T Cells: Warriors of SARS-CoV-2 Infection.

Trends Immunol 2021 01 13;42(1):18-30. Epub 2020 Nov 13.

Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Napoli, Italy. Electronic address:

Severe infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is characterized by massive cytokine release and T cell loss. The exaggerated host immune response, incapable of viral clearance, instead aggravates respiratory distress, as well as cardiac, and/or damage to other organs. The mortality pattern of SARS-CoV-2 infection, higher in older versus younger adults and almost absent in children, is possibly caused by the effects of age and pre-existing comorbidities on innate and adaptive immunity. Here, we speculate that the abnormal and excessive immune response to SARS-CoV-2 infection partly depends on T cell immunological memory, which is more pronounced in adults compared with children, and may significantly contribute to immunopathology and massive collateral damage in coronavirus disease 2019 (COVID-19) patients.
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http://dx.doi.org/10.1016/j.it.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664351PMC
January 2021

Immunometabolism of regulatory T cells in cancer.

Mol Aspects Med 2021 02 26;77:100936. Epub 2020 Nov 26.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy; Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale Delle Ricerche (IEOS-CNR), 80131, Napoli, Italy. Electronic address:

Regulatory T (Treg) cells are known to orchestrate the regulatory mechanisms aimed at suppressing pathological auto-reactive immune responses and are thus key in ensuring the maintenance of immune homeostasis. On the other hand, the presence of Treg cells with enhanced suppressive capability in a plethora of human cancers represents a major obstacle to an effective anti-cancer immune response. A relevant research effort has thus been dedicated to comprehend Treg cell biology, leading to a continuously refining characterization of their phenotype and function and unveiling the central role of metabolism in ensuring Treg cell fitness in cancer. Here we focus on how the peculiar biochemical characteristics of the tumor microenvironment actually support Treg cell metabolic activation and favor their selective survival and proliferation. Moreover, we examine the key metabolic pathways that may become useful targets of novel treatments directed at hampering tumor resident Treg cell proficiency, thus representing the next research frontier in cancer immunotherapy.
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http://dx.doi.org/10.1016/j.mam.2020.100936DOI Listing
February 2021

CD31 Extracellular Vesicles From Patients With Type 2 Diabetes Shuttle a miRNA Signature Associated With Cardiovascular Complications.

Diabetes 2021 01 23;70(1):240-254. Epub 2020 Oct 23.

IRCCS MultiMedica, Milan, Italy.

Innovative biomarkers are needed to improve the management of patients with type 2 diabetes mellitus (T2DM). Blood circulating miRNAs have been proposed as a potential tool to detect T2DM complications, but the lack of tissue specificity, among other reasons, has hampered their translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs have been proposed as an alternative approach. Here, we adapted an immunomagnetic bead-based method to isolate plasma CD31 EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker characterization showed that CD31 EVs were also positive for a range of markers typical of both platelets and activated endothelial cells. After characterization, we quantified 11 candidate miRNAs associated with vascular performance and shuttled by CD31 EVs in a large ( = 218) cross-sectional cohort of patients categorized as having T2DM without complications, having T2DM with complications, and control subjects. We found that 10 of the tested miRNAs are affected by T2DM, while the signature composed by miR-146a, -320a, -422a, and -451a efficiently identified T2DM patients with complications. Furthermore, another CD31 EV-shuttled miRNA signature, i.e., miR-155, -320a, -342-3p, -376, and -422a, detected T2DM patients with a previous major adverse cardiovascular event. Many of these miRNAs significantly correlate with clinical variables held to play a key role in the development of complications. In addition, we show that CD31 EVs from patients with T2DM are able to promote the expression of selected inflammatory mRNAs, i.e., , , and , when administered to endothelial cells in vitro. Overall, these data suggest that the miRNA cargo of plasma CD31 EVs is largely affected by T2DM and related complications, encouraging further research to explore the diagnostic potential and the functional role of these alterations.
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http://dx.doi.org/10.2337/db20-0199DOI Listing
January 2021

CD4 T Cell Defects in a Mulibrey Patient With Specific Mutations.

Front Immunol 2020 18;11:1742. Epub 2020 Sep 18.

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore", Consiglio Nazionale delle Ricerche, Naples, Italy.

Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the () gene, encoding for TRIM37 a member of the TRIM E3 ubiquitin ligase protein family. MUL patients are characterized by growth retardation, dysmorphic features, and a wide range of abnormalities affecting different organs. However, T-cell abnormalities have not been observed in MUL subjects, to date. Here we described the immunological features of a MUL child carrying recently identified mutations, a 17q22 deletion of maternal origin combined with a variant of paternal origin. Here we found quantitative and functional defects in CD4 T cells from this MUL case. Low levels of TRIM37 protein were specifically detected in CD4 T cells of MUL patient and associated with their altered proliferation and cytokine production. Of note, both CD4 and CD8 T lymphocytes of MUL child displayed an effector memory phenotype compared with healthy children. This clinical case research highlighted the possible role of TRIM37 in the control of immune cell number and function, especially in CD4 T cells. Finally, this study may contribute to the novel mechanistic studies aim of identifying, in depth, the role of the TRIM37 protein in the immune system.
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http://dx.doi.org/10.3389/fimmu.2020.01742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530177PMC
April 2021

Where Mitochondria Meet Autoimmunity: The Treg Cell Link.

Cell Metab 2020 10;32(4):507-509

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address:

Although a crucial role for mitochondrial metabolism in controlling T regulatory (Treg) cell function has been recognized, its contribution during autoimmunity has not yet been fully elucidated. In this issue of Cell Metabolism, Alissafi and colleagues demonstrate that during autoimmunity, Treg cell functional alterations associate with mitochondrial oxidative stress, dysfunctional mitophagy, and enhanced DNA damage response, culminating with their cell death.
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http://dx.doi.org/10.1016/j.cmet.2020.08.006DOI Listing
October 2020

A Single Nucleotide ADA Genetic Variant Is Associated to Central Inflammation and Clinical Presentation in MS: Implications for Cladribine Treatment.

Genes (Basel) 2020 09 30;11(10). Epub 2020 Sep 30.

Unit of Neurology, IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli (IS), Italy.

In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets. We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced disability and increased CSF levels of TNF, IL-5 and RANTES was observed. In addition, lower CSF levels of the anti-inflammatory cytokine IL-10 were found. Finally, the presence of the C allele was associated with a tendency of increased lymphocyte count. In MS patients, ADA SNP rs244072 is associated with CSF inflammation and disability. The selective targeting of the ADA pathway through cladribine tablet therapy could be effective in MS by acting on a pathogenically relevant biological mechanism.
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http://dx.doi.org/10.3390/genes11101152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601054PMC
September 2020

The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution.

J Clin Invest 2020 12;130(12):6261-6277

Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

FOXP3+CD4+ regulatory T cells (Tregs) are critical for immune homeostasis and respond to local tissue cues, which control their stability and function. We explored here whether developmental endothelial locus-1 (DEL-1), which, like Tregs, increases during resolution of inflammation, promotes Treg responses. DEL-1 enhanced Treg numbers and function at barrier sites (oral and lung mucosa). The underlying mechanism was dissected using mice lacking DEL-1 or expressing a point mutant thereof, or mice with T cell-specific deletion of the transcription factor RUNX1, identified by RNA sequencing analysis of the DEL-1-induced Treg transcriptome. Specifically, through interaction with αvβ3 integrin, DEL-1 promoted induction of RUNX1-dependent FOXP3 expression and conferred stability of FOXP3 expression upon Treg restimulation in the absence of exogenous TGF-β1. Consistently, DEL-1 enhanced the demethylation of the Treg-specific demethylated region (TSDR) in the mouse Foxp3 gene and the suppressive function of sorted induced Tregs. Similarly, DEL-1 increased RUNX1 and FOXP3 expression in human conventional T cells, promoting their conversion into induced Tregs with increased TSDR demethylation, enhanced stability, and suppressive activity. We thus uncovered a DEL-1/αvβ3/RUNX1 axis that promotes Treg responses at barrier sites and offers therapeutic options for modulating inflammatory/autoimmune disorders.
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http://dx.doi.org/10.1172/JCI137530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685741PMC
December 2020

Immunometabolism and autoimmunity.

Curr Opin Immunol 2020 12 9;67:10-17. Epub 2020 Aug 9.

Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy; Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy. Electronic address:

Over the last few years, immune cell metabolism has become one of the most stimulating areas of investigation in the field of immunology. Compelling evidence has revealed that metabolic pathways are closely associated to cell functions and immune cells adopt defined metabolic programs to sustain their activity and respond to micro-environmental demands. It is now clear that alterations in cell metabolism can favour dysregulation typical of autoreactive immune cells, thus sustaining loss of immunological self-tolerance. In this short review, we highlight the main metabolic alterations associated with both innate and adaptive immune cells in autoimmune conditions, such as multiple sclerosis (MS) and type 1 diabetes (T1D). We also summarize recent findings reporting the use of pharmacological agents, which modulate the immunometabolism to possibly control immune responses during autoimmune disorders.
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http://dx.doi.org/10.1016/j.coi.2020.07.002DOI Listing
December 2020
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