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Abstract: This study tests the hypothesis that in isolated human polymorphonuclear leukocytes (PMN) adrenergic ligands can affect neutrophil extracellular trap (NET) formation. We have previously shown that, in PMN, adrenaline (A), through the activation of adrenergic receptors (AR), reduces stimulus‐dependent cell activation; we have, therefore, planned to investigate if AR are involved in NET production. PMN were obtained from venous blood of healthy subject. The ability of adrenergic ligands to affect reactive oxygen species (ROS) production, NET production, and cell migration was investigated in cells cultured under resting conditions or after activation with N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP), LPS, or IL‐8. Stimuli‐induced NET production measured as ROS, microscopic evaluation, and elastase production was reverted by A and this effect was blocked by the selective β2–AR antagonist ICI‐118,551. The stimulus‐induced ROS generation and migration was prevented by A and by isoprenaline (ISO), and these effects were counteracted only by ICI‐118,551 and not by the other two selective ligands for the β1 and β3–AR. Finally, the presence of the β–ARs on PMN was confirmed, by means of microscopy and flow cytometry. The data of the present study suggest that adrenergic compounds, through the interaction of mainly β2–AR, are able to affect neutrophil functions. These data are suggestive of a possible therapeutic role of β2–AR ligands (in addition to their classical use), promoting the possible therapeutic relevance of adrenergic system in the modulation of innate immunity proposing their possible use as anti‐inflammatory drugs. [ABSTRACT FROM AUTHOR]

Purpose To identify factors predicting success and analyze critically the status of microsurgical double-layer vasovasostomy using predictive models. Methods A cohort of 263 patients treated at our institution for vasectomy reversal between 1986 and 2010 was included in our study, and the literature was reviewed. Inclusion criteria were previous bilateral vasectomy and presence of at least two postoperative semen analyses; patients reporting pregnancy without a postoperative semen analysis were excluded. A double-layer, microscope-assisted, tension-free anastomosis vasovasostomy was performed approximating mucosa to mucosa and muscle to muscle with a 10-0 non-absorbable suture. A multivariate logistic regression backward stepwise model was used to predict combined success, and a predictive model was calculated with remaining variables. Results Mean age was of 41.6 years (SD 7.1); mean duration of obstruction 7.2 years (SD 6.7). On multivariate analysis, uni- or bilateral granuloma and Silber grade of I-III were variable identified predicting higher probability to success (OR 3.105; 95% CI 1.108-8.702; p = 0.031 and OR 4.795; 95% CI 2.117-10.860; p < 0.001, respectively). Conclusions Based on our results, some factors predicting success after vasovasostomy surgery are known but others remain unknown; our predictive model may easily predict patency and success after this surgery and offers a concrete assistance in counseling patients. [ABSTRACT FROM AUTHOR]

The dual potential to promote tolerance or inflammation to self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. Previous results have shown that stimulation of dopamine receptor D5 (DRD5) in DCs potentiates their inflammatory behaviour, favouring the development of experimental autoimmune encephalomyelitis (EAE). Here, we aimed to decipher the underlying mechanism and to test its relevance in multiple sclerosis (MS) patients. Our data shows that DRD5-deficiency confined to DCs in EAE mice resulted in reduced frequencies of CD4+ T-cell subsets with inflammatory potential in the central nervous system, including not only Th1 and Th17 cells but also granulocyte-macrophage colony-stimulating factor producers. Importantly, ex vivo depletion of dopamine from DCs resulted in a dramatic reduction of EAE severity, highlighting the relevance of an autocrine loop promoting inflammation in vivo. Mechanistic analyses indicated that DRD5-signalling in both mouse DCs and human monocytes involves the attenuation of signal transducer and activator of transcription 3-activation, a transcription factor that limits the production of the inflammatory cytokines interleukin (IL)-12 and IL-23. Furthermore, we found an exacerbated expression of all dopamine receptors in peripheral blood pro-inflammatory monocytes obtained from MS patients. These findings illustrate a novel mechanism by which myeloid antigen-presenting cells may trigger the onset of their inflammatory behaviour promoting the development of autoimmunity. [ABSTRACT FROM AUTHOR]

Summary: The neurotransmitter dopamine (DA) has prominent effects in the immune system and between the immune cells, CD4+ regulatory T (Treg) lymphocytes, a specialized T‐cell subset crucial for the control of immune homeostasis, are especially sensitive to DA. Dopaminergic receptors (DR) are grouped into two families according to their pharmacological profile and main second messenger coupling: the D1‐like (D1 and D5), which activate adenylate cyclase, and the D2‐like (D2, D3 and D4), which inhibit adenylate cyclase and exist in several variants that have been associated to clinical conditions such as schizophrenia, bipolar disorder, substance abuse and addiction. We aimed to examine, in venous blood samples from healthy volunteers, the relationship between the arbitrary DR score and DR functional responses in human lymphocytes. All the samples were genotyped for selected DR gene variants (DRD1: rs4532 and rs686; DRD2: rs1800497 and rs6277; DRD3: rs6280; DRD4: rs747302 and seven 48‐base pair variable number tandem repeat (VNTR)) and a DR score was attributed to each participant. We have also tested whether DR gene polymorphisms might affect Treg cell ability to suppress effector T‐cell function. To our knowledge, this is the first study showing a correlation between DR gene variants and human T lymphocyte function. The main results are that both D1‐like and D2‐like DR are functionally active in human lymphocytes, although the D1‐like DR stimulation results in stronger effects in comparison to the D2‐like DR stimulation. In addition, it seems that the DR genetic profile may affect the ability of lymphocytes to respond to dopaminergic agents. More investigations are needed about the possible clinical relevance of such findings. [ABSTRACT FROM AUTHOR]

Dopamine (DA) is a neurotransmitter in the central nervous system as well as in peripheral tissues. Emerging evidence however points to DA also as a key transmitter between the nervous system and the immune system as well as a mediator produced and released by immune cells themselves. Dopaminergic pathways have received so far extensive attention in the adaptive branch of the immune system, where they play a role in health and disease such as multiple sclerosis, rheumatoid arthritis, cancer, and Parkinson's disease. Comparatively little is known about DA and the innate immune response, although DA may affect innate immune system cells such as dendritic cells, macrophages, microglia, and neutrophils. The present review aims at providing a complete and exhaustive summary of currently available evidence about DA and innate immunity, and to become a reference for anyone potentially interested in the fields of immunology, neurosciences and pharmacology. A wide array of dopaminergic drugs is used in therapeutics for non-immune indications, such as Parkinson's disease, hyperprolactinemia, shock, hypertension, with a usually favorable therapeutic index, and they might be relatively easily repurposed for immune-mediated disease, thus leading to innovative treatments at low price, with benefit for patients as well as for the healthcare systems. [ABSTRACT FROM AUTHOR]