The weight of leptin in immunity Cava, Antonio La; Matarese, Giuseppe
Nature reviews. Immunology,
05/2004, Letnik:
4, Številka:
5
Journal Article
Recenzirano
Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is ...sexually dimorphic - that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.
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.
Intracellular metabolism is central to cell activity and function. CD4(+)CD25(+) regulatory T cells (Tregs) that express the transcription factor FOXP3 play a pivotal role in the maintenance of ...immune tolerance to self. Recent studies showed that the metabolism and function of Tregs are influenced significantly by local environmental conditions and the availability of certain metabolites. It also was reported that defined metabolic programs associate with Treg differentiation, expression of FOXP3, and phenotype stabilization. This article reviews how metabolism modulates FOXP3 expression and Treg function, what environmental factors are involved, and how metabolic manipulation could alter Treg frequency and function in physiopathologic conditions.
Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been ...previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.
The T cell receptor (TCR) repertoire is diverse, thus allowing recognition of a wide range of pathogens by T cells. In humans, the study of the formation of TCR repertoires is problematic because of ...the difficulty in performing investigations in vivo. In this issue of the JCI, Khosravi-Maharlooei and colleagues describe a new humanized mouse model that allows direct investigations on this topic. Using high-throughput and single-cell TCR-complementarity-determining region 3 β (TCR-CDR3β) sequencing, the authors were able to demonstrate that human thymic selection is a major driver of TCR sequence sharing, also implicating a preferential selection of shared cross-reactive CDR3βs during repertoire formation.
Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) ...cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.
Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) ...cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain.
Oleotourism (olive oil tourism) is a new form of gastronomic tourism that satisfies increasingly challenging tourist demand, especially in the wake of the pandemic and for tourists who seek not only ...quality food products but also a safe environment to enjoy their chosen activity. Córdoba is a province in southern Spain where olives play a very important role, accounting for 50% of its cultivated area, and whose agricultural activity can be complemented with tourism due to its 189 oil mills that can welcome visitors for oil tasting. However, this type of tourism is not seeing an expected boom. This research analyzes, through a varimax analysis, the factors that attract and drive oleotourists as well as the components of such tourism. As a result, four principal components related to tourists and tourism offers were obtained, finding a high degree of satisfaction of oleotourist with the routes explored as well as a lack of knowledge of this type of tourism in international markets.
Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to ...measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post‐ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus‐pituitary‐adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.—Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang,Z.,Yu,C.,Zhang,F.,Song,L.,Dong,J.‐F.,LaCava,A.,Sheth,K.N.,Shi,F.‐D.Organ‐andcell‐specificimmune responses are associated with the outcomes of intracerebral hemorrhage. FASEB J. 32,220‐229 (2018). www.fasebj.org
Human CD4+CD25hiFoxp3+CD127− Treg and CD4+CD25−Foxp3− Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg ...and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells.
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•Ex vivo human Treg cells are highly glycolytic and proliferating•Ex vivo human Tconv cells use fatty-acid oxidation (FAO) and are non-proliferating•In vitro proliferation of human Treg cells requires both glycolysis and FAO•In vitro proliferation of human Tconv cells relies mainly on glycolysis
The proteomic signature of human Treg and Tconv cells and their functional specialization is poorly understood. Matarese and colleagues identified metabolic pathway signatures that suggest a highly-tuned balance between glucose and fatty-acid oxidation impacting functions of in vitro versus ex vivo human Treg and Tconv cells.
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