Red blood cell transfusion is associated with an increased risk of splanchnic vein thrombosis in patients with cirrhosis.

BACKGROUND: Haemorrhage and coagulation disorders are common complications in cirrhotic patients, which cause blood products transfusion, and mounting evidence suggested that red blood cells (RBCs) were associated with pathologic thrombosis and RBC transfusion increased the risk of venous thromboembolism (VTE). AIMS: The aim of the study was to investigate the association of RBC transfusion with splanchnic vein thrombosis (SVT) in cirrhotic patients. MATERIALS & METHODS: We retrospectively reviewed patients with cirrhosis admitted in the Hunan Provincial People's Hospital between January 2010 and September 2020. Demographic data, the development of SVT, blood transfusion product type and RBC transfusion dose were collected. Multivariate logistic regression analyses and propensity matching analysis (PSM) were performed to identify the association between RBC transfusion and development of SVT. RESULTS: A total of 4479 patients with cirrhosis were enrolled in the study. SVT occurred in 48 (12.4%) cirrhotic patients in RBC transfusion group, and 233 (5.7%) cirrhotic patients in non-RBC transfusion group. RBC transfusion was significantly associated with an increased risk of SVT (unadjusted odds ratio [OR] 2.345, 95% confidence interval [CI] 1.686-3.262, p < 0.001). Notably, this association remained robust after PSM, and the volume of RBC transfusion was associated with SVT in a dose-dependent manner. CONCLUSION: This study suggested that RBC transfusion was associated with an increased risk of SVT in cirrhotic patients. High quality clinical study will be needed to further validate the association between RBC transfusion and SVT.

Development and validation of a nomogram for early assessment the severity of acute pancreatitis.

BACKGROUND: Acute pancreatitis is an acute inflammatory disorder of the pancreas, and severe acute pancreatitis is associated with high mortality. Early assessment the severity of AP has an important significance for improving clinical outcomes. Our object aimed to develop a nomogram with high simplicity and rapidity for predicting the severity of acute pancreatitis. METHODS: Patients admitted to the Hunan Provincial People's Hospital within 72 h from onset of AP from January 2010 and December 2020 were enrolled to establish a nomogram. Independent predictors were determined using univariate and multivariate analysis and then assembled to construct a predicting nomogram. The performance of proposed nomogram was evaluated by Brier score and Harrell's concordance index (C-index). Meanwhile, clinical data of AP patients from January 2021 to January 2022 were collected for external validation. RESULTS: Album (OR 0.891, 95%CI 0.867-0.917), calcium (OR 0.151, 95%CI 0.084-0.273), neutrophil to lymphocyte ratio (OR 1.055, 95%CI 1.023-1.088) and systemic inflammatory response syndrome (OR 6.292, 95%CI 4.459-8.879) were identified as independent factors of SAP after univariate and multivariate analysis (p < .05). A predictive nomogram was accordingly established using these four independent variables. The internally verified C-index was 0.796 (95% CI 0.773-0.818), Brier score was 0.138. The externally verified C index was 0.820 (95% CI 0.754-0.887). CONCLUSION: A nomogram for predicting the severity of AP was well developed, it may be of great significance for clinicians to quickly assess the progress of AP and choose more-targeted strategies.

Acute promyelocytic leukemia with FIP1L1::RARA fusion gene: The clinical utility of transcriptome sequencing and bioinformatic analyses.

Background: Acute promyelocytic leukemia (APL) is typically characterized by the presence of coagulopathy and the PML::RARA fusion gene. The FIP1L1::RARA has been reported as a novel fusion gene, but studies on its pathogenesis are limited. Objectives: A FIP1L1::RARA fusion in a child finally diagnosed as APL was reported. RNA sequencing (RNA-seq) of six patients (three cases of acute lymphoblastic leukemia (ALL), one case of myelodysplastic syndrome (MDS), one case of acute megakaryoblastic leukemia (M7), and one case of APL with FIP1L1::RARA) were performed. Methods: Transcriptome analysis of six patients was performed by RNA-seq. The heat map was used for showing the RNA expression profile, the volcano plot for identifying differential expression genes (DEGs), and the KEGG Orthology-Based Annotation System (KOBAS) online biological information database for KEGG pathway enrichment analysis. Results: Obvious differences between APL with FIP1L1::RARA and hematologic malignancies were identified. 1060 common differentially expressed genes (co-DEGs) were detected between APL with FIP1L1::RARA vs ALL and APL with FIP1L1::RARA vs myeloid neoplasms (MDS, M7), the up-regulated genes were mainly mapped into platelet activation, cancer, AMPK signaling pathway, PI3K-Akt signaling pathway, and MAPK signaling pathway. The down-regulated genes were significantly associated with TNF signaling pathway, Rap1 signaling pathway, Age-RAGE signaling pathway, and apoptosis. Conclusion: A FIP1L1::RARA fusion in a child finally diagnosed as APL was reported. RNA-seq may provide a new diagnostic method when RARA rearrangements fail to be identified by conventional methods. In the analysis of co-DEGs between case vs ALL and case vs myeloid neoplasms, the up-regulated and down-regulated genes were enriched in different signaling pathways. Further experimental studies are needed to identify pathogenesis and treatment for APL with FIP1L1::RARA.

Survival processing effect in memory under semantic divided attention.

Past research demonstrated enhanced memory for information encoded with relevance to a survival scenario compared to a control scenario, an effect referred to as the survival processing effect in memory. This effect has been explained by a proximate mechanism hypothesis (i.e., survival processing enables deep elaborative processing that promotes memory). In support of this hypothesis, past research found that, during encoding, the survival processing effect was largely intact under a perceptual or low-load secondary task condition but eliminated under a high-load secondary task condition. To test semantic encoding as a possible proximate mechanism, the current study assesses the impact of high-load and low-load divided attention tasks that require semantic processing of digits on the survival processing effect. Seventy-two young adults rated words for their relevance to two survival scenarios (i.e., grassland and mountain) and one non-survival control scenario (i.e., cruise), while completing a concurrent high-load or low-load semantic digit-monitoring task. No survival processing effect was found in either condition. The results suggest that semantic encoding probably serves as a proximate mechanism for the survival processing effect in memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Retracted: The Effect of Bilingualism on Older Adults' Inhibitory Control: A Meta-Analysis.

BACKGROUND AND OBJECTIVES: The effect bilingualism has on older adults' inhibitory control has been extensively investigated, yet there is continued controversy regarding whether older adult bilinguals show superior inhibitory control compared with monolinguals. The objective of the current meta-analysis was to examine the reliability and magnitude of the bilingualism effect on older adults' inhibitory control as measured by the Simon and Stroop tasks. In addition, we examined whether individual characteristics moderate the bilingual advantage in inhibition, including age (young-old vs old-old), age of second language acquisition, immigrant status, language proficiency, and frequency of language use. RESEARCH DESIGN AND METHODS: A total of 22 samples for the Simon task and 14 samples for the Stroop task were derived from 28 published and unpublished articles (32 independent samples, with 4 of these samples using more than 1 task) and were analyzed in 2 separate meta-analyses. RESULTS: Analyses revealed a reliable effect of bilingualism on older adults' performance on the Simon (g = 0.60) and Stroop (g = 0.27) tasks. Interestingly, individual characteristics did not moderate the association between bilingualism and older adults' inhibitory control. DISCUSSION AND IMPLICATIONS: The results suggest there is a bilingual advantage in inhibitory control for older bilinguals compared with older monolinguals, regardless of the individual characteristics previously thought to moderate this effect. Based on these findings, bilingualism may protect inhibitory control from normal cognitive decline with age.

ß-Carotene prevents weaning-induced intestinal inflammation by modulating gut microbiota in piglets.

OBJECTIVE: Weaning is an important stage in the life of young mammals, which is associated with intestinal inflammation, gut microbiota disorders, and even death. ß-Carotene displays anti-inflammatory and antioxidant activities, which can prevent the development of inflammatory diseases. However, whether ß-carotene can affect intestinal microbiota remains unclear. METHODS: Twenty-four piglets were distributed into four groups: the normal suckling group (Con), the weaning group (WG), the weaning+ß-carotene (40 mg/kg) group (LCBC), and the weaning+ß-carotene (80 mg/kg) group (HCBC). The serum, jejunum, colon, and faeces were collected separately from each group. The effects of ß-carotene on the phenotype, overall structure, and composition of gut microbiota were assessed in weaning piglets. RESULTS: The results showed that ß-carotene improved the growth performance, intestinal morphology and relieved inflammation. Furthermore, ß-carotene significantly decreased the species from phyla Bacteroidetes and the genus Prevotella, and Blautia, and increased the species from the phyla Firmicutes and the genera p-75-a5, and Parabacteroides compared to the WG group. Spearman's correlation analysis showed that Prevotella and Blautia were positively correlated, and Parabacteroides and Synergistes were negatively correlated with the levels of interleukin-1ß (IL-1ß), IL-6, and tumour necrosis factor-α (TNF-α), while p-75-a5 showed negative correlation with IL-6 in serum samples from piglets. CONCLUSION: These findings indicate that ß-carotene could alleviate weaning-induced intestinal inflammation by modulating gut microbiota in piglets. Prevotella may be a potential target of ß-carotene in alleviating the weaning-induced intestinal inflammation in piglets.

ß-Carotene attenuates LPS-induced rat intestinal inflammation via modulating autophagy and regulating the JAK2/STAT3 and JNK/p38 MAPK signaling pathways.

Inflammation is a protective response of the immune defense system and inflammatory response could be regulated by autophagy. ß-Carotene has shown anti-inflammatory potential. However, whether ß-carotene could alleviate rat intestinal inflammation by modulating autophagy and its anti-inflammation underlying mechanisms remain unknown. In this study, we found that ß-carotene significantly reduced (p < .05) the production of nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor (TNF)-α, and interleukin-1ß (IL-1ß) levels by the Griess reaction and enzyme-linked immunosorbent assay (ELISA), and we found that ß-carotene significantly suppressed (p < .05) the mRNA expression levels of IL-1ß and TNF-α by RT-PCR. In addition, H&E staining revealed that ß-carotene could improve intestinal morphology and cell morphology. Furthermore, the levels of signaling proteins of microtubule-associated protein light chain 3 (LC3), AKT, Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3), nuclear factor-kappa B (NF-κB), and c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) were detected by Western blot analysis. We found that ß-carotene significantly attenuated (p < .05) the related signaling proteins activated by lipopolysaccharide (LPS) stimulation in rats. Moreover, this conclusion was also verified in intestinal epithelial cell (IEC)-6. 3-Methyladenine (3-MA) is widely used as inhibitor of autophagy via its inhibitory effect on class III PI3K. Simultaneously, pretreatment of 3-MA suppressed the inhibiting effects of ß-carotene on the related signaling proteins. This study demonstrates that ß-carotene could attenuate the LPS-induced intestinal inflammation in rats via modulating autophagy and regulating the JAK2/STAT3 and JNK/p38 MAPK signaling pathways. We also found the same phenomenon when we verified the results with the IEC-6 cells. These findings provide new insights into improving the nutritional value of basic diets and enhancing immune performance. PRACTICAL APPLICATIONS: ß-Carotene is a generally acknowledged natural carotenoid nutrient that exhibits provitamin A activity, and it is widely found in fruits or vegetables. Our study provide a new insight into the anti-inflammatory mechanism of ß-carotene. Treatment with ß-carotene can be used for the beneficial effect against LPS-induced inflammation damage. This study not only lays the foundation for the related research on the anti-inflammatory properties of ß-carotene in vitro and in rat models, but also holds important significance in the field of food.

ß-carotene attenuates weaning-induced apoptosis via inhibition of PERK-CHOP and IRE1-JNK/p38 MAPK signalling pathways in piglet jejunum.

Weaning may cause oxidative injury, immune response impairment, apoptosis and other injuries in piglets. Oxidative and endoplasmic reticulum stress (ERS) can elicit inflammatory responses, and persistent oxidative and ERS also may lead to apoptotic cascades, which is associated with the pathogenesis of multiple diseases. ß-carotene, a natural carotenoid, has potential anti-inflammatory and antioxidant functions. However, the effect of ß-carotene on apoptosis in weaned piglets and the detailed molecular mechanism remain unclear. In this study, we found that ß-carotene decreased malondialdehyde (MDA) levels and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in piglet serum. ß-carotene could inhibit the mRNA levels of caspase-3 significantly, but had no significant inhibitory effect of the mRNA levels of caspase-9 and caspase-12 in the piglet jejunum. In addition, ß-carotene decreased the activation of GRP78, CHOP, and JNK/p38 MAPK and the ratio of Bax/Bcl-2. Furthermore, ß-carotene had a significant influence on the activation of ERS and apoptosis-related signals in TG-induced IPEC-J2. In the present study, ß-carotene pre-treatment attenuated the ratio of Bax/Bcl-2 and prevented TG-induced increases in the level of PERK-CHOP and IRE1-JNK/p38 MAPK pathway activation in a dose-dependent manner. Overall, these findings indicate that ß-carotene may protect weaning-induced apoptosis through inhibiting ERS.

Zinc ions increase GH signaling ability through regulation of available plasma membrane-localized GHR.

It is well known that zinc ion (Zn2+ ) can regulate the biological activity of growth hormone (GH). However, until now, the mechanism by which Zn2+ regulates GH biological activity remains unclear. In the current study, we first performed molecular docking between Zn2+ and porcine GH (pGH) using computational biology. We then explored the effect of Zn2+ on the GH signaling ability in the cell model expressing porcine growth hormone receptor (GHR). It was found that the phosphorylation levels of Janus kinase 2, signal transducers and activators of transcription 5/3/1, and GHR increased significantly under Zn2+ treatment, indicating that Zn2+ can enhance the signaling ability of GH/GHR. On this basis, we further explored how Zn2+ regulates the biological activity of GH/GHR. The results showed that downregulation and turnover of GHR changed under Zn2+ /pGH treatment. Zn2+ enhanced the membrane residence time of pGH/GHR and delayed GHR downregulation. Further investigation showed that the internalization dynamic of pGH/GHR was changed by Zn2+ , which prolonged the residence time of pGH/GHR in the cell membrane. These factors acted together to upregulate the signaling of GH/GHR. This study lays a foundation for further exploration of the biological effects of Zn2+ on GH.

Age-related changes to oscillatory dynamics during maintenance and retrieval in a relational memory task.

In aging, structural and/or functional brain changes may precede changes in cognitive performance. We previously showed that despite having hippocampal volumes similar to those of younger adults, older adults showed oscillatory changes during the encoding phase of a short-delay visuospatial memory task that required spatial relations among objects to be bound across time (Rondina et al., 2016). The present work provides a complementary set of analyses to examine age-related changes in oscillatory activity during maintenance and retrieval of those spatial relations in order to provide a comprehensive examination of the neural dynamics that support memory function in aging. Participants were presented with three study objects sequentially. Following a delay (maintenance phase), the objects were re-presented simultaneously and participants had to determine whether the relative spatial relations among the objects had been maintained (retrieval phase). Older adults had similar task accuracy, but slower response times, compared to younger adults. Both groups showed a decrease in theta (2-7Hz), alpha (9-14Hz), and beta (15-30Hz) power during the maintenance phase. During the retrieval phase, younger adults showed theta and beta power increases that predicted greater task accuracy, whereas older adults showed a widespread decrease in each of the three frequency ranges that predicted longer response latencies. Older adults also showed distinct patterns of behaviour-related activity depending on whether the analysis was time-locked to the onset of the stimulus or to the onset of the response during the test phase. These findings suggest that older adults may experience declines in relational binding and/or comparison processes that are reflected in oscillatory changes prior to structural decline.

The effect of pet therapy on the physiological and subjective stress response: A meta-analysis.

Studies have reported that exposure to pet therapy (PT) can reduce physiological and subjective stress and anxiety levels. The aim of this meta-analysis is to examine the efficacy of PT as a method for reducing physiological stress levels (blood pressure and heart rate) and subjective stress and anxiety scores (self-reported stress/anxiety). Further, we examined the effects of sample characteristics and modifications to the PT (different age groups and health status of participants across samples, whether a stressor was present, and individual versus group PT) as potential moderators of the relationship between PT and stress reactivity. Our searches incorporated articles published from May 2017 and earlier in PsycINFO, MEDLINE, and PubMed. This meta-analysis included 28 articles with 34 independent samples and contained a total of 1,310 participants. Using a random effects model, we determined that significant differences occurred in heart rate, self-reported anxiety, and self-reported stress after PT exposure compared with before PT. However, we did not detect significant differences in blood pressure after PT. Sample characteristics and modifications to the PT significantly moderated the effect of PT on stress responses. Our results suggest that PT can be an effective program for reducing stress reactivity.

Portable eyetracking-based assessment of memory decline.

INTRODUCTION: Preferential viewing of novel stimuli in the Visual Paired Comparison task has provided a useful marker of memory and medial temporal lobe function. We created a portable version of the VPC (P-VPC) and contrasted P-VPC metrics against the Montreal Cognitive Assessment (MoCA) in healthy adults, to assess the validity and reliability of the P-VPC as an indicator of memory function across age. A supplementary case series was conducted with individuals diagnosed with Alzheimer's disease (AD) and other dementias, to provide a preliminary illustration of the P-VPC's use as a measure in clinical populations. METHOD: Participants (n = 207) were tested using the P-VPC. Individuals were familiarized with a set of objects, which were each presented alongside a novel object in the test phase. Novelty viewing scores were compared to MoCA scores to index concurrent validity. Item analyses were conducted as a test of internal reliability of the P-VPC. A complementary clinical case series was conducted with AD (n = 4) and dementia (n = 5) participants, who were tested using the P-VPC and further compared to healthy age-matched participants. RESULTS: Preferential viewing decreased with age in healthy participants, and was positively correlated with MoCA scores. Compared to the MoCA, P-VPC scores did not differ based on education and/or whether English was spoken as the native language. Item analyses revealed acceptable internal consistency. P-VPC viewing percentiles of healthy participants were modeled as a function of age, and illustrated that individuals of the clinical case series diagnosed with AD scored in below-average percentiles, while those with dementia did not score below-average. CONCLUSION: Good concurrent validity and acceptable internal reliability were observed, and P-VPC scores were not confounded by education or language experience. Low performance was observed in individuals with clinically diagnosed AD, suggesting that the P-VPC may be a potential tool for screening memory decline.

Pim-1 inhibitor attenuates trinitrobenzene sulphonic acid induced colitis in the mice.

Pim-1 kinase has been implicated in inflammatory bowel disease (IBD). This study aimed to evaluate the application of Pim-1 inhibitor (PIM-Inh) for the treatment of IBD. Mouse model of IBD was established by the treatment with trinitrobenzene sulphonic acid (TNBS). The results showed that disease activity index score was significantly decreased, colon length was significantly increased while Wallace score and pathological score were significantly decreased after PIM-Inh treatment compared to TNBS model group. In addition, GATA3 and ROR-γt mRNA and protein levels significantly increased but Foxp3 mRNA and protein levels significantly decreased in mice with TNBS treatment compared to mice without TNBS treatment. Administration of PIM-Inh caused significant decreases in GATA3, T-bet and ROR-γt mRNA and protein levels as well as significant increases in FOXP3 mRNA and protein levels. In conclusion, our data suggest that Pim-1 kinase inhibitor could attenuate IBD by promoting T-cell differentiation into Foxp3+ regulatory T-cells and is a promising agent for IBD therapy.

Stereotype Threat Effects on Older Adults' Episodic and Working Memory: A Meta-Analysis.

Background and Objectives: Prior research has shown that exposure to negative age-based stereotype threat (ST) can undermine older adults' memory performance. The objective of the current meta-analysis was to examine the reliability and magnitude of ST effects on older adults' episodic and working memory performance-two forms of memory that typically show the greatest age-related declines. In addition, we examined potential moderators of age-based ST including type of ST manipulation, type and timing of memory task, participant age and education level. Research Design and Method: A total of 23 samples for episodic memory and 15 samples for working memory were derived from 19 published and 4 unpublished articles and analyzed in two separate meta-analyses. Results: Analyses revealed a reliable effect of ST on both older adults' episodic (d = 0.373) and working memory performance (d = 0.253). Interestingly, the age-based ST effect was only significant when blatant ST manipulations were used with episodic memory tasks or when subtle ST manipulations were used with working memory tasks. Moreover, within episodic memory, the ST effect only reached significance for recall but not cued-recall or recognition performance, and for immediate but not delayed tests of memory. Neither age nor level of education moderated the association between ST and older adults' memory performance. Discussion and Implications: These results highlight the vulnerability of both older adults' episodic and working memory performance to age-based ST. When measuring older adults' memory performance in a research context, we must therefore be wary of exposing participants to common stereotypes about aging and memory.

Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase.

Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.

Age-related changes to oscillatory dynamics in hippocampal and neocortical networks.

Recent models of hippocampal function have emphasized its role in relational binding - the ability to form lasting representations regarding the relations among distinct elements or items which can support memory performance, even over brief delays (e.g., several seconds). The present study examined the extent to which aging is associated with changes in the recruitment of oscillatory activity within hippocampal and neocortical regions to support relational binding performance on a short delay visuospatial memory task. Structural magnetic resonance imaging and MEG were used to characterize potential age-related changes in hippocampal volume, oscillatory activity, and subsequent memory performance, and the relationships among them. Participants were required to bind the relative visuospatial positions of objects that were presented singly across time. Subsequently, the objects were re-presented simultaneously, and participants were required to indicate whether the relative spatial positions among the objects had been maintained. Older and younger adults demonstrated similar task accuracy, and older adults had preserved hippocampal volumes relative to younger adults. Age-group differences were found in pre-stimulus theta (∼5Hz) and beta (∼20Hz) oscillations, and this pre-stimulus activity was related to hippocampal volumes in younger adults. Age-group differences were also found in the recruitment of oscillatory activity from the pre-stimulus period to the task. Only younger adults showed a task-related change in theta power that was predictive of memory performance. In contrast, older adults demonstrated task-related alpha (∼10Hz) oscillatory power changes that were not observed in younger adults. These findings provide novel evidence for the role of the hippocampus and functionally connected regions in relational binding that is disrupted in aging. The present findings are discussed in the context of current models regarding the cognitive neuroscience of aging.

Activation of the STING adaptor attenuates experimental autoimmune encephalitis.

Cytosolic DNA sensing activates the stimulator of IFN genes (STING) adaptor to induce IFN type I (IFN-αß) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance breakdown, leading to autoimmunity. In this study, we show that systemic treatments with DNA nanoparticles (DNPs) induced potent immune regulatory responses via STING signaling that suppressed experimental autoimmune encephalitis (EAE) when administered to mice after immunization with myelin oligodendrocyte glycoprotein (MOG), at EAE onset, or at peak disease severity. DNP treatments attenuated infiltration of effector T cells into the CNS and suppressed innate and adaptive immune responses to myelin oligodendrocyte glycoprotein immunization in spleen. Therapeutic responses were not observed in mice treated with cargo DNA or cationic polymers alone, indicating that DNP uptake and cargo DNA sensing by cells with regulatory functions was essential for therapeutic responses to manifest. Intact STING and IFN-αß receptor genes, but not IFN-γ receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on IDO enzyme activity in hematopoietic cells. Thus, DNPs and cyclic diguanylate monophosphate attenuate EAE by inducing dominant T cell regulatory responses via the STING/IFN-αß/IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING/IFN-αß pathway in either stimulating or suppressing autoimmunity and identify STING-activating reagents as a novel class of immune modulatory drugs.

Cutting edge: DNA sensing via the STING adaptor in myeloid dendritic cells induces potent tolerogenic responses.

Cytosolic DNA sensing via the stimulator of IFN genes (STING) adaptor incites autoimmunity by inducing type I IFN (IFN-αß). In this study, we show that DNA is also sensed via STING to suppress immunity by inducing IDO. STING gene ablation abolished IFN-αß and IDO induction by dendritic cells (DCs) after DNA nanoparticle (DNP) treatment. Marginal zone macrophages, some DCs, and myeloid cells ingested DNPs, but CD11b(+) DCs were the only cells to express IFN-ß, whereas CD11b(+) non-DCs were major IL-1ß producers. STING ablation also abolished DNP-induced regulatory responses by DCs and regulatory T cells, and hallmark regulatory responses to apoptotic cells were also abrogated. Moreover, systemic cyclic diguanylate monophosphate treatment to activate STING induced selective IFN-ß expression by CD11b(+) DCs and suppressed Th1 responses to immunization. Thus, previously unrecognized functional diversity among physiologic innate immune cells regarding DNA sensing via STING is pivotal in driving immune responses to DNA.