Giuseppe Matarese

Immunological functions of leptin and adiponectin

Recent years have seen several advances in our understanding of the functions of adipose tissue regarding not only the energy storage, but also the regulation of complex metabolic and endocrine functions. In this context, leptin and adiponectin, the two most abundant adipocyte products, represent one of the best example of adipocytokines involved in the control of energy expenditure, lipid and carbohydrate metabolism as well as in the regulation of immune responses. Leptin and adiponectin secretion is counter-regulated in vivo, in relation to degree of adiposity, since plasma leptin concentrations are significantly elevated in obese subjects in proportion to body mass index while adiponectin secretion decreases in relation to the amount of adipose tissue. In this review we focus on the main biological activities of leptin and adiponectin on the lipid and carbohydrate metabolism and on their contribute in regulation of innate and adaptive immune responses.

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25−FOXP3− effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin–mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.

Leptin in autoimmune diseases

The past twenty years of research on leptin has 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, diabetes, or degenerative disease including autoimmunity and cancer. In this review, we provide an overview of recent advances on the role of leptin in the pathogenesis of several autoimmune disorders that may be of particular relevance in the modulation of the autoimmune attack through metabolic-based therapeutic approaches.

Role of adipokines signaling in the modulation of T cells function.

The field that links immunity and metabolism is rapidly expanding. Apparently non-immunological disorders such as obesity and type 2 diabetes have been linked to immune dysregulation, suggesting that metabolic alterations can be induced by or be consequence of an altered self-immune tolerance. In this context, adipose tissue produces and releases a variety of pro-inflammatory and anti-inflammatory factors, termed “adipokines,” which can be considered as the bridge between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events leading to metabolic syndrome, inflammatory, and/or autoimmune conditions. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, modulation of immune responses, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism, and so on. This report aims to discuss some of the recent topics of adipocytokine research and their related signaling pathways, that may be of particular importance as could lead to effective therapeutic strategies for obesity-associated diseases.

Neuro-endocrine networks controlling immune system in health and disease

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.

At the crossroad of T cells, adipose tissue, and diabetes.

The study of how different intracellular metabolic signaling pathways impact the control of self‐immune tolerance and how metabolic dysregulation in overweight, obesity, and diabetes is able to alter self‐immune tolerance are topics of intensive investigation. Recent evidence suggests that metabolic and autoimmune diseases, both characterized by chronic inflammation and an altered self‐immune tolerance, are more common in affluent countries. The reasons for such phenomena are still not completely understood, but the ‘metabolic pressure’ induced by nutritional overload, typical of more developed countries, seems to play a role. In this context, the discovery of the adipose tissue‐derived hormone leptin has shed fundamental insights on how these processes might occur. We believe that there is a strong relationship among leptin, metabolic state, and immunological self‐tolerance. We hypothesize that the leptin‐induced metabolic pressure sets the basis for an exaggerated immuno‐inflammatory response to altered self or non‐self, leading to chronic inflammation, metabolic dysregulation, and autoimmunity in subjects with risk factors (i.e. genetic predisposition, environment, sex, infectious agents, etc). Capitalizing on our joint effort and trans‐disciplinary expertise in metabolism, self‐tolerance, and autoimmune diseases, this review highlights key questions on the basic mechanisms governing immune tolerance in the context of metabolic and autoimmune disease susceptibility.

Resveratrol couples apoptosis with autophagy in UVB-irradiated HaCaT cells.

UVB radiation causes about 90% of non-melanoma skin cancers by damaging DNA either directly or indirectly by increasing levels of reactive oxygen species (ROS). Skin, chronically exposed to both endogenous and environmental pro-oxidant agents, contains a well-organised system of chemical and enzymatic antioxidants. However, increased or prolonged free radical action can overwhelm ROS defence mechanisms, contributing to the development of cutaneous diseases. Thus, new strategies for skin protection comprise the use of food antioxidants to counteract oxidative stress. Resveratrol, a phytoalexin from grape, has gained a great interest for its ability to influence several biological mechanisms like redox balance, cell proliferation, signal transduction pathways, immune and inflammatory response. Therefore, the potential of resveratrol to modify skin cell response to UVB exposure could turn out to be a useful option to protect skin from sunlight-induced degenerative diseases. To investigate into this matter, HaCaT cells, a largely used model for human skin keratinocytes, were treated with 25 or 100 µM resveratrol for 2 and 24 hours prior to UVB irradiation (10 to 100 mJ/cm2). Cell viability and molecular markers of proliferation, oxidative stress, apoptosis, and autophagy were analyzed. In HaCaT cells resveratrol pretreatment: reduces UVB-induced ROS formation, enhances the detrimental effect of UVB on HaCaT cell vitality, increases UVB-induced caspase 8, PARP cleavage, and induces autophagy. These findings suggest that resveratrol could exert photochemopreventive effects by enhancing UVB-induced apoptosis and by inducing autophagy, thus reducing the odds that damaged cells could escape programmed cell death and initiate malignant transformation.

Leptin promotes lupus T-cell autoimmunity.

In systemic lupus erythematosus (SLE), the impairment in apoptosis can facilitate the initiation and maintenance of autoimmune responses to self antigens. Here we show that the adipocytokine leptin, which is abnormally elevated in SLE, promotes the survival and proliferation of autoreactive T-cells in mice with an autoreactive T-cell repertoire, including (NZB x NZW)F1 lupus-prone mice. This ability of leptin to promote lupus T-cell autoimmunity suggests the possibility of a therapeutic targeting of leptin in SLE.

Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia

We report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide‐excision repair (NER) and basal transcription. Our patient showed neurological and immune system abnormalities, including CD4u2003+ lymphopenia never previously reported in TTD patients. In vitro immunological studies revealed a marked reduction in T‐cell proliferation in response to mitogens and CD3 cross‐linking which was partially recovered by the addition of anti‐CD28 antibody or exogenous interleukin‐2. The patients T cells displayed alterations in T‐cell receptor (TCR/CD3) proximal signalling characterized by marked reduction in Lck kinase activity coupled with a constitutive hyperactivation of Fyn kinase. Despite these alterations, normal levels of Lck and Fyn proteins were detected. The role of antigen‐presenting cells (APCs) in the pathogenesis of the T‐cell defect was investigated by analysing dendritic cells (DCs) generated from the patients blood monocytes. In these cells, flow cytometry revealed significantly reduced expression of the CD86 co‐stimulatory molecules and HLA glycoproteins. In addition, the patients DCs showed a decreased ability to stimulate naive T lymphocytes. Overall, the results of our study suggest that a defective TFIIH complex might result in alterations in T cells and DC functions leading to a severe immunodeficiency.

Leptin modulates autophagy in human CD4+CD25- conventional T cells

Objective In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4+CD25− conventional (Tconv) T cells. Results 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. Materials/methods 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. Conclusions 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.