Immuno-moodulin: A new anxiogenic factor produced by Annexin-A1 transgenic autoimmune-prone T cells.

Patients suffering from autoimmune diseases are more susceptible to mental disorders yet, the existence of specific cellular and molecular mechanisms behind the co-morbidity of these pathologies is far from being fully elucidated. By generating transgenic mice overexpressing Annexin-A1 exclusively in T cells to study its impact in models of autoimmune diseases, we made the unpredicted observation of an increased level of anxiety. Gene microarray of Annexin-A1 CD4+ T cells identified a novel anxiogenic factor, a small protein of approximately 21 kDa encoded by the gene 2610019F03Rik which we named Immuno-moodulin. Neutralizing antibodies against Immuno-moodulin reverted the behavioral phenotype of Annexin-A1 transgenic mice and lowered the basal levels of anxiety in wild type mice; moreover, we also found that patients suffering from obsessive compulsive disorders show high levels of Imood in their peripheral mononuclear cells. We thus identify this protein as a novel peripheral determinant that modulates anxiety behavior. Therapies targeting Immuno-moodulin may lead to a new type of treatment for mental disorders through regulation of the functions of the immune system, rather than directly acting on the nervous system.

'As above, so below' examining the interplay between emotion and the immune system.

While the concept of a palpable relationship between our mental and physical well-being is certainly not new, it is only in the light of modern scientific research that we have begun to realize how deeply connected our emotional and immune states may be. We begin this review with a series of studies demonstrating how four fundamental emotional responses: anger, anxiety, mirth and relaxation are able modulate cytokine production and cellular responses to a variety of immune stimuli. These modulations are shown to be either detrimental or beneficial to a patient's health dependent on the context and duration of the emotion. We also discuss the reverse, highlighting research demonstrating how the loss of key immune cells such as T lymphocytes in clinical and animal studies can negatively impact both emotional well-being and cognition. Additionally, to give a more complete picture of the manifold pathways that link emotion and the immune system, we give a brief overview of the influence the digestive system has upon mental and immunological health. Finally, throughout this review we attempt to highlight the therapeutic potential of this burgeoning field of research in both the diagnosis and treatment of immune and disorders. As well as identifying some of the key obstacles the field must address in order to put this potential into practice.

Angiotensin II induces tumor necrosis factor-α expression and release from cultured human podocytes.

OBJECTIVE: High levels of both angiotensin (Ang) II and tumor necrosis factor (TNF)-α have been implicated in the pathogenesis of glomerular injury by affecting podocytes. The aim of this study was to investigate the Ang II-TNF-α relationship in human podocytes. METHODS: Immortalized podocytes were exposed to Ang II for 6 days in the absence or presence of either losartan or PD123,319 (both at 100 nM), AT(1) and AT(2) receptor antagonists, respectively. RESULTS: Ang II, after at least 72 h of repeated treatment, increased basal TNFA gene expression and cytokine release with a biphasic pattern and maximum response at 10 nM. Losartan dampened the effects of Ang II on TNF-α production throughout the experimental period, demonstrating an AT(1) receptor contribution. PD123,319 affected the second TNF-α production peak, showing also an AT(2) receptor contribution. Moreover, Ang II causes tumor necrosis factor receptor (TNFR) 1 and TNFR2 over-expression in a time-dependent manner. The functional interaction between Ang II and TNF-α was demonstrated when the pro-proliferative effect of Ang II was antagonized by a neutralizing TNF-α antibody. CONCLUSIONS: Our results show a functional interaction between Ang II and TNF-α and implicate this cytokine as a mediator in Ang II long-term pathoadaptive podocytes changes.

PPARgamma stimulation promotes neurite outgrowth in SH-SY5Y human neuroblastoma cells.

Several evidences indicate that PPARgamma stimulation promotes neuronal differentiation. However, to date, no data describe the effects of PPARgamma agonists on neurite outgrowth. Here we have evaluated the effects of pioglitazone, a synthetic PPARgamma agonist, on differentiation and neurite outgrowth in SH-SY5Y human neuroblastoma cells. Our results show that pioglitazone promotes cell differentiation and the outgrowth of cell processes in a concentration-dependent manner with the maximal effect at 100 nM-1 microM. It significantly increases both the mean process length and the percentage of neurite-bearing cells. In addition, these effects are accompanied by significant activation of p42 and p44 mitogen-activated protein kinases. In conclusion, albeit preliminary, these findings suggest the possibility that PPARgamma stimulation may contribute to the development and maintenance of a proper neuronal connectivity within neuronal networks.

Impact of Enriched Environment on Murine T Cell Differentiation and Gene Expression Profile.

T cells are known to be plastic and to change their phenotype according to the cellular and biochemical milieu they are embedded in. In this study, we transposed this concept at a macroscopic level assessing whether changes in the environmental housing conditions of C57/BL6 mice would influence the phenotype and function of T cells. Our study shows that exposure to 2 weeks in an enriched environment (EE) does not impact the T cell repertoire in vivo and causes no changes in the early TCR-driven activation events of these cells. Surprisingly, however, T cells from enriched mice showed a unique T helper effector cell phenotype upon differentiation in vitro. This was featured by a significant reduction in their ability to produce IFN-γ and by an increased release of IL-10 and IL-17. Microarray analysis of these cells also revealed a unique gene fingerprint with key signaling pathways involved in autoimmunity being modulated. Together, our results provide first evidence for a specific effect of EE on T cell differentiation and its associated changes in gene expression profile. In addition, our study sheds new light on the possible mechanisms by which changes in environmental factors can significantly influence the immune response of the host and favor the resolution of the inflammatory response.

Impaired sense of smell and altered olfactory system in RAG-1(-∕-) immunodeficient mice.

Immune deficiencies are often associated with a number of physical manifestations including loss of sense of smell and an increased level of anxiety. We have previously shown that T and B cell-deficient recombinase activating gene (RAG-1)(-∕-) knockout mice have an increased level of anxiety-like behavior and altered gene expression involved in olfaction. In this study, we expanded these findings by testing the structure and functional development of the olfactory system in RAG-1 (-∕-) mice. Our results show that these mice have a reduced engagement in different types of odors and this phenotype is associated with disorganized architecture of glomerular tissue and atrophy of the main olfactory epithelium. Most intriguingly this defect manifests specifically in adult age and is not due to impairment in the patterning of the olfactory neuron staining at the embryo stage. Together these findings provide a formerly unreported biological evidence for an altered function of the olfactory system in RAG-1 (-∕-) mice.

Massage-like stroking boosts the immune system in mice.

Recent clinical evidence suggests that the therapeutic effect of massage involves the immune system and that this can be exploited as an adjunct therapy together with standard drug-based approaches. In this study, we investigated the mechanisms behind these effects exploring the immunomodulatory function of stroking as a surrogate of massage-like therapy in mice. C57/BL6 mice were stroked daily for 8 days either with a soft brush or directly with a gloved hand and then analysed for differences in their immune repertoire compared to control non-stroked mice. Our results show that hand- but not brush-stroked mice demonstrated a significant increase in thymic and splenic T cell number (p < 0.05; p < 0.01). These effects were not associated with significant changes in CD4/CD8 lineage commitment or activation profile. The boosting effects on T cell repertoire of massage-like therapy were associated with a decreased noradrenergic innervation of lymphoid organs and counteracted the immunosuppressive effect of hydrocortisone in vivo. Together our results in mice support the hypothesis that massage-like therapies might be of therapeutic value in the treatment of immunodeficiencies and related disorders and suggest a reduction of the inhibitory noradrenergic tone in lymphoid organs as one of the possible explanations for their immunomodulatory function.

Smile--It's in your blood!

Emotions and feelings are the bricks of our social life and yet we often forget that they have a significant impact on our physical wellbeing. Indeed, a growing number of studies have shown that both an imbalanced or improved emotional state can significantly influence the way our immune system responds. In this commentary, we have summarized the most recent studies on the effects of different types of emotional states on the immune system and we have also explored the effects of mood modulator approaches on the immune response. We hope this commentary will prompt scientists and clinicians to think about the therapeutic value and potential of emotions and feelings in immune-related diseases. At the same time, we think that this commentary will shed some light on the scientific truth behind the very famous expression "It's in my blood" when we talk about feelings and personality.

Novel immunological targets in rheumatic diseases: clues from current therapies.

Many years have elapsed since the discovery of immunomodulators as effective therapeutics for the treatment of rheumatic diseases, and we are still learning about their various mechanisms of action. Here, we provide a concise overview of the most recent discoveries in this field of research, focusing in particular on signaling pathways targeted by therapeutics currently used in the clinic. We highlight areas of investigation that could potentially be explored for the development of new classes of antirheumatic drugs.

Formyl peptide receptor as a novel therapeutic target for anxiety-related disorders.

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface.

Pro-inflammatory and pathogenic properties of Annexin-A1: the whole is greater than the sum of its parts.

According to Aristotle, "The whole is greater than the sum of its parts" and yet, although a long time has passed still, we seem to struggle to accept this universal concept. Searching in the literature for the biological function of Annexin-A1, one would find a wealth of information on its homeostatic and protective anti-inflammatory effects. However, very little has been said on its emerging role in a wide variety of pathological conditions ranging from cancer to autoimmunity. In this commentary, we will focus our attention on this novel pro-inflammatory and pathogenic "dark side" of Annexin-A1. We will summarize our current understanding of the signaling pathways regulated by this protein and link it to clinical and experimental evidences. Finally we will discuss assets and limitations of Annexin-A1 therapeutic strategies. Most importantly, we hope that this commentary will provide scientific support to "controversial" findings one might encounter while studying this fascinating protein.

Emotional change-associated T cell mobilization at the early stage of a mouse model of multiple sclerosis.

Autoimmune diseases like multiple sclerosis (MS) are known to be associated with debilitating emotional disorders that manifest long before the flaring of motor dysfunctions. Given the emerging role of T cells in controlling both emotions and autoimmunity, in this study we explored possible correlation between T cell activation and changes in emotional behavior in a mouse model of MS. Our results showed a significant increase in blood circulating T cells as soon as at day 4 post immunization. This lymphocytosis remained stable with time and preceded the infiltration of T cell in the CNS. The kinetic of T cell entry in the blood matched the kinetic of changes in behavior measured using the open field test. Treatment with glatiramer acetate, a well-known immunomodulatory drug for MS, suppressed behavioral changes while retaining the T cells in the draining lymph nodes. Together these results provide evidence of a positive correlation between the emigration of T cells in circulation and changes in emotions during chronic inflammatory diseases. The validation of these findings in the clinic might help to better understand the cause of the emotional and psychological burden of patients suffering MS or other autoimmune diseases. Most importantly our study suggests novel therapeutic venues for the treatment of the emotional changes associated with autoimmunity.

Protective effects of peroxisome proliferator-activated receptor agonists on human podocytes: proposed mechanisms of action.

BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptor (PPAR) agonists exert anti-albuminuric effects. However, the nephroprotective effects of these drugs remain to be fully understood. We have investigated whether gemfibrozil, GW0742 and pioglitazone protect human podocytes against nutrient deprivation (ND)-induced cell death and the role of mitochondrial biogenesis as a cytoprotective process. EXPERIMENTAL APPROACH: Immortalized human podocytes were pre-treated with the PPAR agonists and exposed to ND (5 h) under normoxia, hypoxia or in the presence of pyruvate. Cell death was measured at the end of the ND and of the recovery phase (24 h). Mitochondrial mass, cytochrome c oxidase (COX) subunits 1 and 4 were measured as markers of mitochondrial cell content, while membrane potential as an index of mitochondrial function. PGC-1α, NRF1 and Tfam expression was studied, as crucial regulators of mitochondrial biogenesis. KEY RESULTS: Cell pre-treatment with gemfibrozil, GW0742, or pioglitazone significantly decreased the ND-induced cell loss, necrosis and apoptosis. These effects were attenuated by hypoxia and potentiated by pyruvate. Pre-treatment with these drugs significantly increased mitochondrial cell content, while it did not affect mitochondrial function. In all these experiments pioglitazone exerted significantly larger effects than gemfibrozil or GW0742. CONCLUSIONS AND IMPLICATIONS: Gemfibrozil, GW0742 and pioglitazone may exert direct protective effects on human podocytes. Mitochondrial biogenesis is a cell response to the PPAR agonists related to their cytoprotective activity. These results provide a mechanistic support to the clinical evidence indicating PPAR agonists as disease-modifying agents for glomerular diseases.

The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury.

BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, and three subtypes (α, ß and γ) have been identified. PPAR activation has been reported to decrease renal injury and markers of glomerular dysfunction in models of renal ischemia/reperfusion (I/R). However, both the I/R effects and the effects of PPAR agonists on podocytes, an integral cellular part of the glomerular filtration barrier, remain to be established. EXPERIMENTAL APPROACH: By using oxygen/glucose deprivation-reoxygenation as an in vitro model that mimics in vivo I/R, the effects of PPAR agonists on podocyte death were compared. Human immortalized podocytes were treated with gemfibrozil, GW0742, pioglitazone or rosiglitazone, as a single or repeated challenge. Cell loss, necrotic and apoptotic cell death were measured. KEY RESULTS: Only the repeated treatment with each PPAR agonist significantly prevented cell death, mainly by decreasing apoptosis. In comparison, in a model of serum deprivation-induced apoptosis, both treatments were effective, although the repeated treatment achieved the more pronounced effect. Finally, our results showed that preservation of Bcl-2, Bax and nephrin expression accompanied the anti-apoptotic effects exerted by PPAR agonists in human podocytes. CONCLUSION AND IMPLICATIONS: These findings contribute to clarification of the pathophysiological role of renal PPARs and suggest that selective PPARα, PPARß or PPARγ agonists may exert similar protective effects on podocytes by decreasing apoptotic cell death.

PPARgamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss.

Peroxisome proliferator-activated receptor (PPAR)gamma stimulation provides protection in several models of neurological disorders, but the mechanisms underlying these effects remain to be fully elucidated. Here we have studied whether two PPARgamma agonists, pioglitazone and rosiglitazone, prevent loss of differentiated SH-SY5Y cells transiently exposed to glucose deprivation (GD). Nanomolar drug concentrations prevented GD-induced cell loss in a concentration- and time-dependent manner. These effects were abolished by malonate, a reversible mitochondrial Complex II inhibitor, while significantly potentiated by pyruvate, thus suggesting that they are related to mitochondrial function. During cell pretreatment, PPARgamma agonists promoted biogenesis of functional mitochondria, as indicated by the up-regulation of PPARgamma coactivator (PGC)-1alpha, NRF1, TFAM, cytochrome c oxidase subunit (CO) I and CO IV, and the increased level of mtDNA, while did not significantly change mitochondrial membrane potential. In addition, the analysis of the concentration-response and time-course curves for the protective effects and the up-regulation of mitochondrial biogenesis markers suggests that mitochondrial biogenesis and cell loss prevention are related effects. In conclusion our data indicate that a prolonged PPARgamma stimulation, by repeated administration of nanomolar pioglitazone or rosiglitazone concentrations, decreases GD-induced loss of differentiated SH-SY5Y cells. In addition, they suggest that mitochondrial biogenesis may contribute to these effects.