Nutritional Status, Dietary Intake, Quality of Life, and Dysphagia in Women With Fibromyalgia.

BACKGROUND: Fibromyalgia syndrome (FMS) is an idiopathic chronic disease characterized by widespread musculoskeletal pain, hyperalgesia, and allodynia that has been recently associated with risk of dysphagia. OBJECTIVE: We aimed to analyze the association between nutritional status, micro- and macronutrient intake, and quality of life (QoL) in a cohort of women with FMS and risk of dysphagia compared to women with FMS without risk of dysphagia. METHODS: A cross-sectional study was conducted in 46 women with FMS. Risk of dysphagia was assessed by the Eating Assessment Tool (EAT-10) and the Volume-Viscosity Swallow Test (V-VST). The Food Frequency Questionnaire and the Swallowing Quality of Life Questionnaire were used to assess dietary intake and QoL, respectively. RESULTS: Thirty women with FMS were at risk for dysphagia (65.21%), assessed by the EAT-10. Based on the V-VST, the frequency of risk of dysphagia was 63.04%. Significant differences in body mass index (BMI) were found between women at risk for dysphagia and those without risk. Women at risk for dysphagia had significantly lower overall QoL scores than those women without risk. No significant differences were found for dietary intake and dysphagia risk. DISCUSSION: Women with FMS at risk for dysphagia have significantly lower BMI values and worse QoL than women without dysphagia risk, supporting the importance of assessing dysphagia in clinical practice in persons with FMS.

Vasodilatory Peripheral Response and Pain Levels following Radiofrequency Stressor Application in Women with Fibromyalgia.

Fibromyalgia (FM) is a syndrome of unknown pathogenesis that presents, among other symptoms, chronic widespread musculoskeletal pain. This study aims to analyze the effects of radiofrequency on core body temperature and the peripheral temperature of the dorsal surfaces and palms of the hands and its association with pain levels in patients with FM. A case-control observational study was conducted with a total of twenty-nine women diagnosed with FM and seventeen healthy women. Capacitive monopolar radiofrequency was applied to the palms of the hands using the Biotronic Advance Develops device. Peripheral hand temperature was analyzed using a thermographic camera, and core body temperature was analyzed with an infrared scanner. Pressure pain thresholds (PPTs) and electrical pain were recorded with an algometer and a Pain Matcher device, respectively. A significant decrease was observed in women with FM in pain electrical threshold (95% CI [0.01-3.56], p = 0.049), electrical pain (95% CI [2.87-10.43], p = 0.002), dominant supraspinatus PPT (95% CI [0.04-0.52], p = 0.023), non-dominant supraspinatus PPT (95% CI [0.03-0.60], p = 0.029), and non-dominant tibial PPT (95% CI [0.05-0.89], p = 0.031). Women with FM have increased hypersensitivity to pain as well as increased peripheral temperature after exposure to a thermal stimulus, such as radiofrequency, which could indicate disorders of their neurovascular response.

Orofacial Pain and Risk of Dysphagia in Women With Fibromyalgia: A Cross-Sectional Observational Study.

OBJECTIVE: This study aims to analyze the frequency of dysphagia risk and swallowing-associated quality of life (QoL) in a sample of women with fibromyalgia syndrome (FMS) and examine the potential relationship between risk of dysphagia and chronic orofacial pain (COP) in a sample of women with FMS. METHOD: A cross-sectional observational study was conducted in 46 women with FMS. COP was assessed by mouth opening, the orofacial visual analog scale (VAS), and the craniofacial pain and disability inventory (CF-PDI). Risk of dysphagia was assessed using the Eating Assessment Tool (EAT-10) and the volume-viscosity swallowing test (V-VST). Swallowing-associated QoL was determined using the Swallowing Quality of Life (SWAL-QOL) questionnaire. RESULTS: Thirty patients were identified as being at risk for dysphagia (65.21%) using the EAT-10 and, according to the SWAL-QOL, 41.30% of patients had alterations in QoL associated with swallowing. The EAT-10 correlated positively with orofacial VAS, CF-PDI-total, CF-PDI-pain and disability, and CF-PDI-jaw-functional status. In relation to SWAL-QOL, negative correlations were observed for orofacial VAS, CF-PDI-total, CF-PDI-pain and disability, and CF-PDI-jaw-functional status. Patients at risk of dysphagia (EAT-10 and V-VST) had significantly higher scores in orofacial VAS (p = .002 and p = .015), CF-PDI-total (p = .006 and p = .014), and CF-PDI-pain and disability (p = .004 and p = .013). CONCLUSIONS: In this sample of women with FMS, we identified a high rate of dysphagia risk. Also, a high percentage of these women presented alterations in QoL associated with swallowing. Patients at risk for dysphagia had significantly higher orofacial VAS and CF-PDI-total scores, supporting the relationship between dysphagia risk and COP in FMS. Further research to establish the need for appropriate assessment referrals in clinical practice to determine whether dysphagia is present in this population is needed.

Association between elasticity of tissue and pain pressure threshold in the tender points present in subjects with fibromyalgia: a cross-sectional study.

Fibromyalgia (FM) is a multicomponent illness and despite its worldwide prevalence, a complete understanding of its aetiology and pathogenesis remains unclear. The goal of the study is to analyze the level of association between elastic properties of tissue measured by strain elastography (SEL) and pain pressure threshold (PPT) in the characteristic painful points described in patients suffering from FM. This was a cross-sectional, observational study. A sample comprised of 42 subjects with FM was recruited from a private care centre. The occiput, low cervical, trapezius, supraspinatus, paraspinous, lateral pectoral, second rib, lateral epicondyle, medial epicondyle, gluteus, greater trochanter, knee, and anterior tibial PPTs were bilaterally assessed using a standard pressure algometer and elastic properties of tissue were evaluated by SEL. Linear regression analysis showed significant associations between SEL and dominant trapezius PPT (ß = 0.487, 95% CI [0.045, 0.930], p = 0.032) after adjustments for the age, body mass index, and menopause status (higher SEL and higher pain sensitivity). No significant associations between SEL and the other PPTs variables were found in women diagnosed with FM. The PPT of the dominant trapezius is associated with SEL measurements in subjects suffering from FM. More studies are required to fully explain the underlying mechanisms.

Serum VEGF and CGRP Biomarkers: Relationships with Pain Intensity, Electric Pain, Pressure Pain Threshold, and Clinical Symptoms in Fibromyalgia-An Observational Study.

Fibromyalgia (FM) is a multifactorial syndrome, mainly characterized by chronic widespread pain, whose physiopathology is yet to be determined. Reliable biomarkers for FM and how they are associated with the symptomatology have not yet been identified. We aimed to examine the relationships among serum vascular endothelial growth factor (VEGF) and calcitonin gene-related peptide (CGRP) levels with clinical manifestations and pain-related variables in women with FM. We conducted an observational case study with forty-seven women diagnosed with FM. Serum VEGF and CGRP levels were spectrophotometrically analyzed. We used questionnaires to measure the impact of FM and the degree of central sensitization, fatigue, and anxiety. We also assessed pain intensity, electric pain threshold and magnitude, and pressure pain threshold (PPT) in tender points. The linear regression analysis adjusting for age, menopause status, and body mass index showed that serum VEGF levels were significantly associated with the PPTs of non-dominant trapezius (ß = 153.418; p = 0.033), non-dominant second metacarpal (ß = 174.676; p = 0.008) and dominant tibialis anterior (ß = 115.080; p = 0.049) in women with FM. We found no association between serum CGRP levels and the variables measured (p ≥ 0.152). Our results suggest that VEGF may be related to pain processing in patients with FM.

scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics.

Dendritic cells and macrophages are integral parts of the innate immune system and gatekeepers against infection. The protozoan pathogen, Toxoplasma gondii, is known to hijack host immune cells and modulate their immune response, making it a compelling model to study host-pathogen interactions. Here we utilize single cell Dual RNA-seq to parse out heterogeneous transcription of mouse bone marrow-derived dendritic cells (BMDCs) infected with two distinct genotypes of T. gondii parasites, over multiple time points post infection. We show that the BMDCs elicit differential responses towards T. gondii infection and that the two parasite lineages distinctly manipulate subpopulations of infected BMDCs. Co-expression networks define host and parasite genes, with implications for modulation of host immunity. Integrative analysis validates previously established immune pathways and additionally, suggests novel candidate genes involved in host-pathogen interactions. Altogether, this study provides a comprehensive resource for characterizing host-pathogen interplay at high-resolution.

Associations among serum VEGF and CGRP levels with the peripheral vascular blood flow of the skin of the hands in women with Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a long-term condition of unknown physiopathology, whose hallmark symptoms are diffuse musculoskeletal chronic pain and fatigue. OBJECTIVES: We aimed to analyze the associations among serum vascular endothelial growth factor (VEGF) and calcitonin gene-related peptide (CGRP) levels with the peripheral temperature of the skin of both hands and the core body temperature in patients with FM and healthy controls. METHODS: We conducted a case-control observational study with fifty-three women diagnosed with FM and twenty-four healthy women. VEGF and CGRP levels were spectrophotometrically analyzed in serum by enzyme-linked immunosorbent assay. We used an infrared thermography camera to assess the peripheral temperature of the skin of the dorsal thumb, index, middle, ring, and pinkie fingertips and dorsal centre as well as the palm thumb, index, middle, ring, and pinkie fingertips, palm centre and thenar and hypothenar eminences of both hands and an infrared thermographic scanner to record the tympanic membrane and axillary temperature. RESULTS: Linear regression analysis adjusting for age, menopause status, and body mass index showed that serum VEGF levels were positively associated with the maximum (ß = 65.942, 95% CI [4.100,127.784], p = 0.037), minimum (ß = 59.216, 95% CI [1.455,116.976], p = 0.045), and mean (ß = 66.923, 95% CI [3.142,130.705], p = 0.040) temperature of the thenar eminence of the non-dominant hand, as well as with the maximum temperature of the hypothenar eminence of the non-dominant hand (ß = 63.607, 95% CI [3.468,123.747], p = 0.039) in women diagnosed with FM. CONCLUSIONS: Mild associations were observed between serum VEGF levels and the peripheral temperature of the skin in hand areas in patients with FM; therefore, it is not possible to establish a clear relationship between this vasoactive molecule and vasodilation of the hands in these patients.

Calcitonin Gene-Related Peptide, Vascular Endothelial Growth Factor, and Clinical Manifestations in Women With Fibromyalgia.

BACKGROUND: Fibromyalgia is a complex illness to diagnose and treat, which significantly impairs patients' quality of life. OBJECTIVES: The study aims were to compare levels of calcitonin gene-related peptide and vascular endothelial growth factor between patients with fibromyalgia and healthy controls and to examine their relationship with the main clinical manifestations of fibromyalgia. METHODS: This case-control study included 42 women diagnosed with fibromyalgia and 22 healthy women. Serum calcitonin gene-related peptide and vascular endothelial growth factor levels were spectrophotometrically analyzed by enzyme-linked immunosorbent assay. Clinical manifestations were assessed by means of self-administered questionnaires, including functional capacity in daily living activities, musculoskeletal pain, fatigue, anxiety, and sleep quality. The predictive value of these parameters in fibromyalgia was determined by receiver operating characteristic curve analysis. RESULTS: Serum calcitonin gene-related peptide levels significantly increased in the fibromyalgia group in comparison to the control group. However, there were no significant differences in vascular endothelial growth factor levels between patients and controls. No significant correlations were found between calcitonin gene-related peptide and vascular endothelial growth factor and the symptoms analyzed. DISCUSSION: Serum calcitonin gene-related peptide levels were dysregulated in women with fibromyalgia and may be a reliable parameter to help diagnose this complex syndrome.

The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages.

Upon pathogen detection, macrophages normally stay sessile in tissues while dendritic cells (DCs) migrate to secondary lymphoid tissues. The obligate intracellular protozoan Toxoplasma gondii exploits the trafficking of mononuclear phagocytes for dissemination via unclear mechanisms. We report that, upon T. gondii infection, macrophages initiate the expression of transcription factors normally attributed to DCs, upregulate CCR7 expression with a chemotactic response, and perform systemic migration when adoptively transferred into mice. We show that parasite effector GRA28, released by the MYR1 secretory pathway, cooperates with host chromatin remodelers in the host cell nucleus to drive the chemotactic migration of parasitized macrophages. During in vivo challenge studies, bone marrow-derived macrophages infected with wild-type T. gondii outcompeted those challenged with MYR1- or GRA28-deficient strains in migrating and reaching secondary organs. This work reveals how an intracellular parasite hijacks chemotaxis in phagocytes and highlights a remarkable migratory plasticity in differentiated cells of the mononuclear phagocyte system.

Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver.

Reconstruction of heterogeneity through single cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years. However, global transcriptional differences across lobular units remain elusive in physical space. Here, we apply Spatial Transcriptomics to perform transcriptomic analysis across sectioned liver tissue. We confirm that the heterogeneity in this complex tissue is predominantly determined by lobular zonation. By introducing novel computational approaches, we enable transcriptional gradient measurements between tissue structures, including several lobules in a variety of orientations. Further, our data suggests the presence of previously transcriptionally uncharacterized structures within liver tissue, contributing to the overall spatial heterogeneity of the organ. This study demonstrates how comprehensive spatial transcriptomic technologies can be used to delineate extensive spatial gene expression patterns in the liver, indicating its future impact for studies of liver function, development and regeneration as well as its potential in pre-clinical and clinical pathology.

GABAergic signaling by cells of the immune system: more the rule than the exception.

Gamma-aminobutyric acid (GABA) is best known as an essential neurotransmitter in the evolved central nervous system (CNS) of vertebrates. However, GABA antedates the development of the CNS as a bioactive molecule in metabolism and stress-coupled responses of prokaryotes, invertebrates and plants. Here, we focus on the emerging findings of GABA signaling in the mammalian immune system. Recent reports show that mononuclear phagocytes and lymphocytes, for instance dendritic cells, microglia, T cells and NK cells, express a GABAergic signaling machinery. Mounting evidence shows that GABA receptor signaling impacts central immune functions, such as cell migration, cytokine secretion, immune cell activation and cytotoxic responses. Furthermore, the GABAergic signaling machinery of leukocytes is implicated in responses to microbial infection and is co-opted by protozoan parasites for colonization of the host. Peripheral GABA signaling is also implicated in inflammatory conditions and diseases, such as type 1 diabetes, rheumatoid arthritis and cancer cell metastasis. Adding to its role in neurotransmission, growing evidence shows that the non-proteinogenic amino acid GABA acts as an intercellular signaling molecule in the immune system and, as an interspecies signaling molecule in host-microbe interactions. Altogether, the data raise the assumption of conserved GABA signaling in a broad range of mammalian cells and diversification of function in the immune system.

Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers.

Multiple cellular processes, such as immune responses and cancer cell metastasis, crucially depend on interconvertible migration modes. However, knowledge is scarce on how infectious agents impact the processes of cell adhesion and migration at restrictive biological barriers. In extracellular matrix, dendritic cells (DCs) infected by the obligate intracellular protozoan Toxoplasma gondii undergo mesenchymal-to-amoeboid transition (MAT) for rapid integrin-independent migration. Here, in a cellular model of the blood-brain barrier, we report that parasitised DCs adhere to polarised endothelium and shift to integrin-dependent motility, accompanied by elevated transendothelial migration (TEM). Upon contact with endothelium, parasitised DCs dramatically reduced velocities and adhered under both static and shear stress conditions, thereby obliterating the infection-induced amoeboid motility displayed in collagen matrix. The motility of adherent parasitised DCs on endothelial monolayers was restored by blockade of ß1 and ß2 integrins or ICAM-1, which conversely reduced motility on collagen-coated surfaces. Moreover, parasitised DCs exhibited enhanced translocation across highly polarised primary murine brain endothelial cell monolayers. Blockade of ß1, ß2 integrins, ICAM-1 and PECAM-1 reduced TEM frequencies. Finally, gene silencing of the pan-integrin-cytoskeleton linker talin (Tln1) or of ß1 integrin (Itgb1) in primary DCs resulted in increased motility on endothelium and decreased TEM. Adding to the paradigms of leukocyte diapedesis, the findings provide novel insights in how an intracellular pathogen impacts the migratory plasticity of leukocytes in response to the cellular environment, to promote infection-related dissemination.

Dietary Intake Assessment, Severity of Symptoms, and Pain in Women with Fibromyalgia.

A cross-sectional study was conducted to assess dietary intake in 92 FMS compared to 96 healthy control patients and to examine the potential associations between daily intake and pain and the severity of symptoms in women with FMS. The tender point count (TPC), the Visual Analog Scale (VAS), and the Revised Fibromyalgia Impact Questionnaire (FIQR) were assessed. FIQ-R correlated negatively with phosphorus (r = -.230, p = .028), iron (r = -.320, p = 0.002), zinc (r = -.238, p = .023), vitamin B1 (r = -.218, p = .038), vitamin B6 (r = -.123, p = .012), folic acid (r = -.250, p = .017), and vitamin C (r = -.217, p = .039). A negative correlation was also found between VAS pain and the intake of vitamin B6 (r = -.322, p = .002). Lower intakes of certain micronutrients correlated with higher scores in FIQ-R and a lower intake of vitamin B6 correlated with higher scores in VAS pain, supporting the potential relevance of these micronutrients in the severity of symptoms and in levels of global pain in FMS women.

Association of core body temperature and peripheral blood flow of the hands with pain intensity, pressure pain hypersensitivity, central sensitization, and fibromyalgia symptoms.

Our aim was to analyse body core temperature and peripheral vascular microcirculation at skin hypothenar eminence of the hands and its relationship to symptoms in fibromyalgia syndrome (FMS). A total of 80 FMS women and 80 healthy women, matched on weight, were enrolled in this case-control study. Thermography and infrared thermometer were used for evaluating the hypothenar regions and core body temperature, respectively. The main outcome measures were pain pressure thresholds (PPTs) and clinical questionnaires. Significant associations were observed between overall impact [ß = 0.033; 95% confidence interval (95%CI) = 0.003, 0.062; p = 0.030], daytime dysfunction (ß = 0.203; 95%CI = 0.011, 0.395; p = 0.039) and reduced activity (ß = 0.045; 95%CI = 0.005, 0.085; p = 0.029) and core body temperature in FMS women. PPTs including greater trochanter dominant (ß = 0.254; 95%CI = 0.003, 0.504; p = 0.047), greater trochanter non-dominant (ß = 0.650; 95%CI = 0.141, 1.159; p = 0.013), as well as sleeping medication (ß = -0.242; 95%CI = -0.471, -0.013; p = 0.039) were also associated with hypothenar eminence temperature. Data highlighted that FMS women showed correlations among body core temperature and hand temperature with the clinical symptoms.

Associations Among Nitric Oxide and Enkephalinases With Fibromyalgia Symptoms.

BACKGROUND: Fibromyalgia (FM) is a complex syndrome of uncertain etiology, characterized by the presence of widespread pain. Both nitric oxide and enkephalinases modulate pain perception. OBJECTIVES: The aim of this study was to evaluate the relationships among serum nitric oxide levels, oxytocinase activity, and enkephalin-degrading aminopeptidase (EDA) activity with pain-related clinical manifestations in women with FM. METHODS: We performed an observational case study in a population of 58 women diagnosed with FM. Serum nitric oxide levels were analyzed by an ozone chemiluminescence-based assay. Both serum oxytocinase and EDA activities were fluorometrically determined. Pain threshold and pain magnitude were evaluated using the PainMatcher. The pressure pain thresholds were measured using a digital pressure algometer. We used a visual analog scale, the Central Sensitization Inventory, the Revised Fibromyalgia Impact Questionnaire, and the Beck Anxiety Inventory to assess the global level of pain, the symptoms associated with the central sensitization syndrome, the severity of FM, and the anxiety level, respectively. RESULTS: Multiple linear regression analysis adjusted by age, body mass index, and menopause status revealed significant associations between nitric oxide levels and dominant occiput pressure pain thresholds, nondominant occiput pressure pain thresholds, and FM effects. Significant associations of oxytocinase activity with the visual analog scale and dominant knee pressure pain thresholds were also found. Moreover, results showed a significant association between high EDA activity levels and dominant second-rib pressure pain thresholds. DISCUSSION: Our data have shown significant relationships of serum nitric oxide levels and oxytocinase and EDA activities with some body pressure pain thresholds, the daily activity level, and the global intensity of pain in women with FM. These results suggest that pain, which is the main symptom of this syndrome, may be related to alterations in nitric oxide levels and in oxytocinase and EDA activities in patients with FM.

Evaluation of sympathetic adrenergic branch of cutaneous neural control throughout thermography and its relationship to nitric oxide levels in patients with fibromyalgia.

BACKGROUND: Fibromyalgia syndrome is defined as a complex disease, characterized by chronic widespread musculoskeletal pain and other symptoms. The factors underlying physiopathology of fibromyalgia are not well understood, complicating its diagnosis and management. OBJECTIVES: To evaluate the peripheral vascular blood flow of the skin of the hands and the core body temperature as indirect measures of sympathetic adrenergic activity of the nervous system and its relationship to nitric oxide levels (NO) in women with fibromyalgia compared with healthy controls. METHODS: Forty-two women with fibromyalgia and 52 healthy women were enrolled in this observational pilot study. We used infrared thermography of the hands and an infrared dermal thermometer to evaluate the peripheral vascular blood flow and tympanic and axillary core body temperature, respectively. We measured NO levels using the ozone chemiluminescence-based method. RESULTS: Two-way analysis of covariance (ANCOVA) showed that the tympanic (P=0.002) and hand temperatures were significantly higher in the patients with fibromyalgia than in the controls (P≤0.001). Significant associations were also found between serum NO levels and minimum temperatures at the dorsal center of the dominant hand (ß=-3.501; 95% confidence interval [CI] -6.805, ­0.198; P= 0.038), maximum temperature (ß=-5.594; 95% CI ­10.106, ­1.081; P=0.016), minimum temperature (ß=-4.090; 95% CI ­7.905, ­0.275; P=0.036), and mean temperature (ß=-5.519; 95% CI ­9.933, ­1.106; P=0.015) of the center of the palm of the non-dominant hand, maximum temperature at the thenar eminence of the dominant hand (ß=-5.800; 95% CI ­10.508, ­1.092; P=0.017), and tympanic temperature (ß=-9.321; 95% CI ­17.974, ­0.669; P=0.035) in the controls. CONCLUSIONS: Our findings indicate that the women with fibromyalgia showed higher tympanic core body and hand temperature than the healthy controls. Moreover, there were negative associations between hand peripheral vasodilation and NO in the healthy women but not in those with fibromyalgia, suggesting a dysfunction of sympathetic cutaneous neural control.

The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13.

Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-κB (NF-κB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-γ (IFN-γ) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.

A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites.

Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.