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Multiple sclerosis (MS) is a highly disabling neurodegenerative autoimmune condition in which an unbalanced immune response plays a critical role. Although the mechanisms remain poorly defined, helminth infections are known to modulate the severity and progression of chronic inflammatory diseases. The tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) have been described as inhibitors of the immune response in various inflammatory settings. We show here that patients with concurrent natural helminth infections and MS condition (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells and their agonist GAS6 in circulating CD11bhigh and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS with a subsequent downregulation of its pathogenic genetic program. Moreover, these CD4+ T cells promoted lower levels of the co-stimulatory molecules CD80, CD86, and CD40 on dendritic cells compared with CD4+ T cells from patients with MS, an effect that was GAS6-dependent. IL-10+ cells from patients with HIMS showed higher GAS6 expression levels than Th17 cells, and inhibition of phosphatidylserine/GAS6 binding led to an expansion of Th17 effector genes. The addition of GAS6 on activated CD4+ T cells from patients with MS restrains the Th17 gene expression signature. This cohort of patients with HIMS unravels a promising regulatory mechanism to dampen the Th17 inflammatory response in autoimmunity. Author summary: Helminths have co-evolved with human civilization, and the rapid exclusion from their environment, in the last few decades, has tremendously affected the immune development and regulation. Moreover, several epidemiological studies have shown an inverse correlation between the exposure of these organisms and the development of autoimmunity in industrialized countries. In this sense, helminth therapy appears to be a promising concept to oppose chronic inflammatory and autoimmune diseases because they are master manipulators of host immunity, albeit the mechanisms remain poorly defined. For this reason, it is essential to decipher the main regulatory pathways to hijack the immune response in the absence of parasite infection. Our research described how helminth infection promotes regulatory mechanisms based on the tyrosine kinase TYRO3, AXL, MERTK (TAM) receptors, and their ligand GAS6 to dampen Th17 development and the inflammatory response in patients with multiple sclerosis (MS), a neurodegenerative autoimmune disorder. We show here that GAS6 plays a critical role in the regulation of pro-inflammatory cytokines, transcriptional programs, and plasticity of IL-17 subset. Our work substantiates the hypothesis that enhancing the TAM axis in a manner similar to helminth infection could be a promising alternative for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract Objective The serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphisms are associated with suicidal behavior; however, prospective studies are scarce. Herein we aim to determine if 5-HTTLPR polymorphisms predict risk of short-term suicide reattempt in a high-risk suicidal sample. We also explore possible mediators or moderators of this relationship. Methods A multicenter prospective cohort study was designed to compare data obtained form 136 patients admitted to the emergency department for current suicidal ideation or a recent suicide attempt. Subjects were clinically evaluated, genotyped, and monitored for a new suicide attempt for 6 months. Results At 6 months of follow up, 21% of the subjects had a new suicide attempt. The frequency of L-allele and L-carrier was higher in reattempters when compared with non-reattempters (55.8% vs. 35.4%, p = 0.01 and 76.9% vs. 54.2%, p = 0.04, respectively). Reattempters also differ from non-reattempters patients with respect to age, history of previous suicide attempts, and age of onset of suicidal behavior. The logistic regression model showed that L-carriers had an odds ratio of 2.8 (95% CI: 1.0–7.6) for reattempts when compared to SS genotype. The adjusted model indicates that this association is not mediated or moderated by impulsivity. Conclusion The 5-HTTLPR polymorphisms predicted short-term risk of suicidal reattempt independently of age and sex. L-carriers have almost three times more risk of relapse when compared with SS carriers. [ABSTRACT FROM AUTHOR]

Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to determine the presence of alpha(1)-adrenoceptor messenger RNA subtypes and extend the pharmacologic characterization of alpha(1)-adrenoceptors involved in human umbilical vein (HUV) contraction.Study Design: Cords (n=124) from healthy patients after term vaginal or cesarean deliveries were used. The vein was carefully dissected out of cords and used for reverse transcription combined with polymerase chain reaction (RT-PCR) to amplify alpha(1)-adrenoceptor transcripts. In isolated organ baths, HUV rings were mounted and cumulative concentration-response curves were constructed either for epinephrine or the selective alpha(1A)-adrenoceptor agonist, A-61603. In other series of experiments, the effects of the selective alpha(1A)- and alpha(1B)-adrenoceptor antagonists (RS-100329 or B8805-033 or spiperone, AH11110A and cyclazosin, respectively) were evaluated to estimate its blocking potencies on epinephrine concentration-response curves.Results: By means of RT-PCR technique alpha(1a)- and alpha(1b)-adrenoceptor transcripts were detected in the HUV. The blocking potency values of RS-100329 or B8805-033 against responses mediated by epinephrine were not consistent with the activation of an alpha(1A)-adrenoceptor population. Moreover, the low potency of the agonist A-61603 was not in accordance with an alpha(1A)-adrenoceptor interaction. On the other hand, the antagonist potencies of spiperone, AH11110A and cyclazosin were in agreement with an interaction on alpha(1B)-adrenoceptor subtype.Conclusion: Although alpha(1a)- and alpha(1b)-adrenoceptor messenger RNAs are detected in the HUV, only alpha(1B)-adrenoceptors are involved in epinephrine vasoconstrictor action. [ABSTRACT FROM AUTHOR]

• This is a longitudinal study of plasma glycerophospholipid PUFAs as predictors of SA. • Low AA levels, but not n-3 PUFA, predicted future suicide attempts. • The protective effects of AA against suicide events were most significant in patients with MDD who were prior attempters. • Total LDL- and HDL-cholesterol did not predict subsequent SA. Polyunsaturated fatty acids (PUFAs) and cholesterol are lipids implicated in suicide risk. We prospectively studied plasma glycerophospholipid PUFAs and cholesterol as putative predictors of suicide attempts. In a multicenter cohort study, we enrolled 123 patients admitted to the emergency department (ED) for suicidal ideation or suicide attempt. Clinical assessments were performed, with follow-up telephone evaluations 6, 12, 18, and 24 months later. Blood samples were obtained in the ED and assayed for PUFAs. Using survival analysis, suicide events were not predicted by eicosapentaenoic acid (EPA, HR : -0.83, 95%CI : 0.39–1.76, p = 0.621) or docosahexaenoic acid (DHA, HR : -0.60, 95%CI : 0.19–1.86, p = 0.371). However, higher arachidonic acid (AA) was a trend for a protective factor (HR =0.30, 95% CI : 0.08–1.08, p = 0.065) in the entire trans-diagnostic sample. This protective effect was significant in all participants with a prior suicide attempt history (n = 85; HR =0.16, 95%CI : 0.04–0.67, p = 0.012), and in the subgroup of attempters with major depressive disorder (MDD; n = 55, HR =0.15, 95%CI :0.03–0.76, p = 0.002). Total LDL- and HDL-cholesterol did not predict subsequent suicide events. AA, but not DHA or EPA, positively correlated with baseline depression severity in MDD patients (r = 0.3, p = 0.006). Contrary to our hypothesis that low n-3 PUFA levels would create risk, we found that while higher AA was associated with greater depression severity at baseline, low AA unexpectedly predicted subsequent suicide attempts, the more so in higher-risk patients. Although surprising, this result agrees with a minority of reports concerning n-6 PUFAs and may represent complex interactions with sample characteristics. [ABSTRACT FROM AUTHOR]

We investigated the contribution of human platelets to macrophage effector properties in the presence of lipopolysaccharide (LPS), as well as the beneficial effects and time frame for platelet transfusion in septic animals. Our results show that platelets sequester both pro-(TNF-α/IL-6) and anti-(IL-10) inflammatory cytokines released by monocytes. Low LPS concentrations (0.01 ng/mL) induced M2 macrophage polarization by decreasing CD64 and augmenting CD206 and CD163 expression; yet, the presence of platelets skewed monocytes toward type 1 macrophage (M1) phenotype in a cell-contact-dependent manner by the glycoprotein Ib (GPIb)-CD11b axis. Accordingly, platelet-licensed macrophages showed increased TNF-α levels, bacterial phagocytic activity, and a reduced healing capability. Platelet transfusion increased inducible nitric oxide synthase (iNOS)+ macrophages, improving bacterial clearance and survival rates in septic mice up to 6 h post-infection, an effect that was abolished by CD11b and GPIb blockade. Our results demonstrate that platelets orchestrate macrophage effector responses, improving the clinical outcome of sepsis in a narrow but relevant time frame. • Platelets sequester pro- and anti-inflammatory cytokines released by monocytes • In the presence of LPS, platelets skew monocytes toward a pro-inflammatory phenotype • During sepsis, platelet transfusion increases iNOS+ macrophages and bacterial clearance • Platelet transfusion increases septic mice survival in a narrow time frame Carestia et al. describe the beneficial role of platelet transfusion for animal survival during sepsis by reprogramming macrophages and fostering antimicrobial functions. The cross-talk between platelets and monocytes that promotes pro-inflammatory macrophages depends on the intimal cellular contact between platelet GPIb and CD11b in the monocyte surface. [ABSTRACT FROM AUTHOR]

The New World arenavirus Junin (JUNV) is the etiological agent of Argentine hemorrhagic fever (AHF). Previous studies of human macrophage infection by the Old-World arenaviruses Mopeia and Lassa showed that while the non-pathogenic Mopeia virus replicates and activates human macrophages, the pathogenic Lassa virus replicates but fails to activate human macrophages. Less is known in regard to the impact of New World arenavirus infection on the human macrophage immune response. Macrophage activation is critical for controlling infections but could also be usurped favoring immune evasion. Therefore, it is crucial to understand how the JUNV infection modulates macrophage plasticity to clarify its role in AHF pathogenesis. With this aim in mind, we compared infection with the attenuated Candid 1 (C#1) or the pathogenic P strains of the JUNV virus in human macrophage cultures. The results showed that both JUNV strains similarly replicated and induced morphological changes as early as 1 day post-infection. However, both strains differentially induced the expression of CD71, the receptor for cell entry, the activation and maturation molecules CD80, CD86, and HLA-DR and selectively modulated cytokine production. Higher levels of TNF-α, IL-10, and IL-12 were detected with C#1 strain, while the P strain induced only higher levels of IL-6. We also found that C#1 strain infection skewed macrophage polarization to M1, whereas the P strain shifted the response to an M2 phenotype. Interestingly, the MERTK receptor, that negatively regulates the immune response, was down-regulated by C#1 strain and up-regulated by P strain infection. Similarly, the target genes of MERTK activation, the cytokine suppressors SOCS1 and SOCS3, were also increased after P strain infection, in addition to IRF-1, that regulates type I IFN levels, which were higher with C#1 compared with P strain infection. Together, this differential activation/polarization pattern of macrophages elicited by P strain suggests a more evasive immune response and may have important implications in the pathogenesis of AHF and underpinning the development of new potential therapeutic strategies., (Copyright © 2019 Ferrer, Thomas, López Ortiz, Errasti, Charo, Romanowski, Gorgojo, Rodriguez, Carrera Silva and Gómez.)

The aim of this study was to test the hypothesis whether MERTK, which is up-regulated in human DCs treated with immunosuppressive agents, is directly involved in modulating T cell activation. MERTK is a member of the TAM family and contributes to regulating innate immune response to ACs by inhibiting DC activation in animal models. However, whether MERTK interacts directly with T cells has not been addressed. Here, we show that MERTK is highly expressed on dex-induced human tol-DCs and participates in their tolerogenic effect. Neutralization of MERTK in allogenic MLR, as well as autologous DC-T cell cultures, leads to increased T cell proliferation and IFN-γ production. Additionally, we identify a previously unrecognized noncell-autonomous regulatory function of MERTK expressed on DCs. Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK ligand PROS1. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine proproliferative mechanism. Collectively, these results suggest that MERTK on DCs controls T cell activation and expansion through the competition for PROS1 interaction with MERTK in the T cells. In conclusion, this report identified MERTK as a potent suppressor of T cell response., (© Society for Leukocyte Biology.)