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Nutrition affects all physiological processes occurring in our body, including those related to the function of the immune system; indeed, metabolism has been closely associated with the differentiation and activity of both innate and adaptive immune cells. While excessive energy intake and adiposity have been demonstrated to cause systemic inflammation, several clinical and experimental evidence show that calorie restriction (CR), not leading to malnutrition, is able to delay aging and exert potent anti-inflammatory effects in different pathological conditions. This review provides an overview of the ability of different CR-related nutritional strategies to control autoimmune, cardiovascular, and infectious diseases, as tested by preclinical studies and human clinical trials, with a specific focus on the immunological aspects of these interventions. In particular, we recapitulate the state of the art on the cellular and molecular mechanisms pertaining to immune cell metabolic rewiring, regulatory T cell expansion, and gut microbiota composition, which possibly underline the beneficial effects of CR. Although studies are still needed to fully evaluate the feasibility and efficacy of the nutritional intervention in clinical practice, the experimental observations discussed here suggest a relevant role of CR in lowering the inflammatory state in a plethora of different pathologies, thus representing a promising therapeutic strategy for the control of human health. [ABSTRACT FROM AUTHOR]

Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the TRIpartite motif (TRIM) 37 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 TRIM37 mutations, a 17q22 deletion of maternal origin combined with a TRIM37 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. [ABSTRACT FROM AUTHOR]

Background: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS., Method: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time., Results: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease -6.98 µg/dL, 95% CI: -28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO + regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks., Conclusions: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS., Trial Registration Number: NCT03539094 ., Competing Interests: Competing interests: LP has received research funding from the National MS Society, the NIH, the Department of Defense and Fondazione Italiana Sclerosi Multipla; she has been funded by Alector and Biogen for a project not related to the one included in this manuscript. She is one of the Editor-in-Chief of Journal of Neuroimmunology. AHC received compensation for consulting for Biogen, EMD Serono, Bristol Myers Squibb, TG Therapeutics, Octave, Genentech, Roche, Novartis, Horizon and Janssen (J&J). AHC was supported by the Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology during this study. CAR received compensation for consulting for CoreTechs.ai, Eli Lilly, Voxelwise, Neurevolution. GFW received compensation for consulting for EMD Serono, Genzyme, Novartis, Sangamo, Roche, Alumis and the US Department of Justice. He has received research grant funding from the NIH, National MS Society, Doris Duke Foundation, US Department of Veterans Affairs, Biogen, EMD Serono and Genentech. He serves on the editorial boards of Neurology: Neuroimmunology & Neuroinflammation and the Journal of Neuroimmunology. He serves on advisory boards for Progentec and Genentech. RTN has consulted for Alexion Pharmaceuticals, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, EMD Serono, Horizon Therapeutics, Novartis, TG Therapeutics. AS receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Department of Defense Congressionally Directed Medical Research Program and is a member of the editorial board for Neurology. She serves as a consultant for Gryphon Bio and Abata Therapeutics. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO) and Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH). She holds the Kenney Marie Dixon-Pickens Distinguished Professorship in Multiple Sclerosis Research., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunometabolism has been demonstrated to control immune tolerance and the pathogenic events leading to autoimmunity. Compelling experimental evidence also suggests that intracellular metabolic programs influence differentiation, phenotype, proliferation, and effector functions of anti-inflammatory CD4+CD25+Foxp3+ regulatory T (Treg) cells. Indeed, alterations in intracellular metabolism associate with quantitative and qualitative impairments of Treg cells in several pathological conditions. In this review, we summarize the most recent advances linking how metabolic pathways control Treg cell homeostasis and their alterations occurring in autoimmunity. Also, we analyze how metabolic manipulations could be employed to restore Treg cell frequency and function with the aim to create novel therapeutic opportunities to halt immune-mediated disorders., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Nutrition affects all physiological processes occurring in our body, including those related to the function of the immune system; indeed, metabolism has been closely associated with the differentiation and activity of both innate and adaptive immune cells. While excessive energy intake and adiposity have been demonstrated to cause systemic inflammation, several clinical and experimental evidence show that calorie restriction (CR), not leading to malnutrition, is able to delay aging and exert potent anti-inflammatory effects in different pathological conditions. This review provides an overview of the ability of different CR-related nutritional strategies to control autoimmune, cardiovascular, and infectious diseases, as tested by preclinical studies and human clinical trials, with a specific focus on the immunological aspects of these interventions. In particular, we recapitulate the state of the art on the cellular and molecular mechanisms pertaining to immune cell metabolic rewiring, regulatory T cell expansion, and gut microbiota composition, which possibly underline the beneficial effects of CR. Although studies are still needed to fully evaluate the feasibility and efficacy of the nutritional intervention in clinical practice, the experimental observations discussed here suggest a relevant role of CR in lowering the inflammatory state in a plethora of different pathologies, thus representing a promising therapeutic strategy for the control of human health., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© Society for Leukocyte Biology.)

Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation., (© Society for Leukocyte Biology.)