bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exosomal miRNAs regulate inflammatory responses (IRM11P.624)
Authors: Alexander Margaret , O'Connell Ryan 
Published: January 2023

Abstract
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Typically, miRNAs are thought to function within the cells where they are transcribed. However, recent data shows that miRNAs are transferred between cells and mediate target gene repression. miR-155 and miR-146a are critical miRNAs that regulate inflammation. We found that miR-155 and miR-146a were released from dendritic cells (DCs) within exosomes and transferred to recipient DCs. These miRNAs were associated with RISC and inhibited their mRNA targets in recipient cells. Following uptake, miRNAs reprogramed the cellular response to endotoxin, where exosomal miR-155 enhanced and miR-146a reduced inflammatory gene expression. miR-155 and miR-146a were also found in exosomes and passed between immune cells in vivo. Additionally, injection of miR-146a containing exosomes delivered miR-146a to various tissues and decreased inflammation in response to endotoxin, while miR-155 containing exosomes had the converse effect. This suggests that exosomal miRNAs could be used as therapy for inflammatory diseases. Further characterization of the loading and functional transfer of miRNAs should make therapeutic approaches more feasible. Additionally, we aim to explore the importance of endogenously transferred miRNAs during immune responses in vivo. Our research will help unravel both the therapeutic potential of exosomal miRNAs and determine the biological relevance of transferred miRNAs in immune responses.
Down regulation of genes related to selenium signaling pathway in in-vivo transmigrated neutrophils from patients with Chronic Kidney Disease (IRM11P.627)
Authors: MANSOURI LADAN , Moshfegh Ali , Hylander Britta , Jacobson Stefan , Lundahl Joachim 
Published: January 2023

Abstract
The most common causes of morbidity in patients with Chronic Kidney Disease (CKD), emerge from the dysregulation of immune system. Granulocytes are less functional, in terms of transmigration to the inflammatory sites. We analyzed the gene expression of neutrophils from peripheral blood, and in-vivo transmigrated neutrophils, collected by skin chamber technique, in CKD patients as well as healthy controls. We found that, transmigration induced a significant change in the gene expression, and kidney failure had different impacts on the gene expression of neutrophils in peripheral blood, and upon in vivo transmigration, comparing to healthy subjects. After Cluster analysis of the significant genes, and subjecting them to signaling pathways, we found selenium signaling pathway as one of those, which were significantly impaired in transmigrated neutrophils from CKD patients. This comprised down regulation of genes such as; Glutathione peroxidase-1 (GPx-1), Superoxide dismutase-2 (SOD2), Peroxiredoxin-1(PRDX1), and Selenoprotein W (SelW) gene. Selenoproteins play a major role in antioxidant defense, thus our results may indicate that the CKD patients have a deficiency in these components, leading to the oxidative stress in neutrophils, and their impairment. These findings, however, warrant further investigation, and we are currently in the process to setup an in-vitro system to analyze the effect of selenium compounds on different functions of neutrophils from CKD patients.
Human tonsil naive B cells and germinal center B cells show distinct behaviors upon contact of antigen in lipid bilayers
Authors: Kwak Kihyuck , Sohn Haewon , Brzostowski Joseph , Manzella-Lapeira Javier , Pierce Susan K 
Published: January 2023

Abstract
During antibody responses to T-dependent antigens B cells undergo clonal expansion and somatic hyper-mutation in the dark zones of germinal centers (GCs) and subsequently undergo isotype switching and affinity based selection in the GC light zones. Only a small portion of B cells survive from GC reactions and differentiate into either plasma cells or memory B cells. However, the mechanism underlying selection within the GC is not fully understood. We compared the behavior of human tonsil naïve (IgD+, CD10−) and GC (IgD−, CD10+) B cells as they engaged antigen (using Light chain specific antibodies as a surrogate antigen) incorporated into planar lipid bilayers using a combination of TIRF and confocal microscopy. We observed marked differences in the cellular dynamics of naïve and GC B cells. Upon touching the antigen-containing bilayer naïve B cells rapidly form B cell receptor (BCR) micro-clusters that grow rapidly with time and signal for Ca++ fluxes. Within five minutes naïve B cells formed stable areas of contact with the bilayers. In contrast, GC B cells only slowly form BCR micro-clusters that grow slowly with time and signal for delayed Ca++ fluxes. Notably, the behavior of GC B cells over the same time period is far more dynamic with only transient interactions with the bilayer and active ruffling in the cells periphery suggesting that the GC B cells in contrast to naïve B cells continue to sample antigen for longer periods of time. Experiments in progress are aimed at relating the observed behaviors to the affinity of naïve and GC B cells for antigen.
Retinoic acid regulates immune responses by promoting IL-22 production and modulating S100 protein in viral hepatitis
Authors: Liang Yuejin , Jie Zuliang , Yi Panpan , Wan Xianxiu , Wang Wei , Tang Hui , Kwota Zakari , Soong Lynn , Cong Yingzi , Zhang Kangling , Sun Jiaren 
Published: January 2023

Abstract
The effector T cell responses promote viral clearance and disease resolution in viral hepatitis, but can also mediate tissue damage; however, much less is known as to how the liver protects itself against the injury. In this study, we have revealed a retinoic acid (RA)-mediated, hepatoprotective mechanism in adenovirus-induced hepatitis in mice. We found that RA treatment promoted hepatoprotective cytokine IL-22, but inhibited the pro-inflammatory factor IL-17, from gd T and double-negative T cells, and that the hepatic IL-17 and IL-22 production were regulated via the mTOR/PI3K signaling pathway. Moreover, we found that RA modulated the magnitude of antigen-specific T cell responses via down-regulating dendritic cell (DC) co-stimulatory molecule expression and its migratory capacity. Mechanistically, RA treatment inhibited Calcium-binding S100 family proteins (S100A4/6/10) and the NF-κB/ERK signaling pathways on DCs. The inhibition of novel S100A4 resulted in impaired DC migration from inflamed tissues to lymph nodes for T cell priming. Collectively, our study has revealed a previously unappreciated role and molecular mechanism of RA in modulating immune responses and protecting the liver from viral hepatitis.
IL-6 influences the balance between M1 and M2 macrophages in a mouse model of irritant contact dermatitis
Authors: Luckett-Chastain Lerin , Calhoun Kaitlin , Schartz Tayler , Gallucci Randle M 
Published: January 2023

Abstract
Irritant contact dermatitis (ICD) is an acute inflammatory response that is ranked the 2nd most prevalent occupational injury associated with workman’s compensation. Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the skin, is closely associated with healing and decreased levels are associated with more severe ICD. The phenotypic nature of the macrophage infiltrate during skin inflammation can greatly influence damage and healing during ICD. The pro-inflammatory, classically activated (M1) macrophage produce cytokines such as IL-6, IL-1, and TNFα, while alternatively activated (M2) macrophages produce IL-10 and TGFβ, and are thought to be associated with tissue repair. IL-6 may play a regulatory role in mediating the M1 versus M2 phenotypic change in skin. To examine the role of IL-6 in ICD, IL-6KO and C57 mice were exposed to benzoalkonium chloride (BKC) for 7 days. IL-6KO mice displayed decreased expression of CD206 (M2) as compared to CD86 (M1) and the ration of CD86:CD206 was significantly increased in IL-6KO mice compared to control. Multiplex protein analysis showed expression of multiple M1-related cytokines such IFN-g, CCL3, CCL4, CCL5, and CCL7 significantly modulated in IL6-KO BKC treated mice compared to C57. Additionally, M2 related cytokine/chemokine receptors IL-4R and CCR1 were significantly dysregulated in IL-6KO BKC treated mice. IL-6 treatment of RAW cells enhanced the expression of CD206 in manner similar to IL-4. Overall, these results further confirm a role for IL-6 in macrophage polarization and could eventually result in the development of therapies for dermatitis based on this cytokines activity.
Novel IL12Rβ1 mutation impairs Th1 response in heterozygote patient.
Authors: Sonder Soren Ulrik , Plassmeyer Matthew , Alpan Oral 
Published: January 2023

Abstract
The interleukin-12 Receptor beta-1 chain (12Rβ1) is a subunit in the functional IL12 and IL23 receptor that binds the IL12 p40 subunit of the IL12 and IL23 heterodimers. Patients that are homozygote for “lack of function” mutations in IL12Rβ1 are mainly characterized by defects in the Th1 response resulting in recurrent and severe disease caused by infections with poorly pathogenic mycobacteria and salmonellae. Family members that are heterozygote for these mutations are clinically unaffected.
Here we describe a case of a 62 year old female patient that is heterozygote for the novel 12Rβ1 mutation Q238E located in the cytokine binding region. The patient has recurrent infections, poor wound healing, osteomyelitis and persistently positive PPD. Lymphocyte count in the lower end of the normal range. Using flow cytometry analysis of whole blood we showed above normal percentages of NK cells and below normal percentages of T-cells. The patients Th1 response was studied by stimulating PBMC from the patient and healthy controls with IL12 and measuring IFNγ in multiple cell types using flow cytometry. The surface expression of IL12Rβ1 does not differ between the patient and controls; however the results demonstrated a reduction in IFNγ producing CD4+ and CD4+/CD45RO+ cells in the patient compared to the controls.
Functional screening for IL12 response may provide a powerful tool in evaluating other patients with recurring infections resulting in more accurate diagnose and efficient treatment.
IL-4R signaling in B cells mediates control of IL-17A dependent emphysema triggered by N. brasiliensis infection.
Authors: Chen Fei , Wu Wenhui , Millman Ariel , Palma Mark J , Gause William C 
Published: January 2023

Abstract
The intestinal nematode parasite, Nippostrongylus brasiliensis (Nb), transiently resides in the lung and causes lung damage, which is then rapidly repaired. However, the repaired lung eventually develops emphysema and the mechanisms contributing to this chronic lung pathology remain poorly defined. Here we show that emphysema, as measured by mean linear intercept measurements (Lm) of alveolar spaces, develops as early as 7 days after Nb inoculation and is associated with increased gene expression of Il17A, neutrophil elastase (ELA), and macrophage matrix metalloproteinase 12 (Mmp12) in the lung. Transfer of Nb-primed neutrophils or macrophages to naïve recipients results in emphysema, and these cells expressed high level of ELA and Mmp12, respectively. Neutralization of IL-17A using anti-IL-17A antibody curbed development of emphysema, and decreased influx of neutrophils in the lung and gene expression of Il17A. Parasite infection in B cell deficient Jh−/− mice results in a more severe emphysema when compared to wild-type mice or FcRγ−/− mice, and is associated with higher numbers of neutrophils and macrophages, as well as increased expression of Il17a, ELA2 and Mmp12 in the lung. Transfer of B lymphocytes from wild-type mice or IL-10−/− mice, but not from IL4Rα−/− mice, to recipient Jh−/− mice can restore control of emphysema and downregulate IL-17A. B cells from lung tissue of Nb-primed wild type but not IL4Rα−/− mice expressed high level of Relmα. Taken together, these data suggest that IL-17A triggers infiltration of neutrophils and macrophages that contribute to chronic emphysema, which is controlled by IL-4R dependent B regulatory cells expressing high levels of Relmα.
Characterization of Th17-like Tregs during late stages of infection with B. pertussis in mice. Possible immunomodulation by type I interferon.
Authors: Smith Andrew A , Jakoush Tarek A , Silva Elvia , You Hana , Wu Victoria , Segal-Abramson Tzvia 
Published: January 2023

Abstract
Whooping cough is a highly contagious respiratory disease caused by Bordetella pertussis (Bp). Recently, the prolonged nature of whooping cough has been associated with a delay in Th17 responses, which are essential to resolve the infection. While investigating the IFNα-driven delay in Th17 responses during Bp infection, we noted a parallel rise of Th17-like Tregs secreting IL-17. Similar T cell hybrids have demonstrated either inflammatory or suppressor function.
In this study we phenotypically and functionally characterized Th17-like Tregs in mice infected with Bp to test the hypothesis that these cells are derived from Tregs and display a suppressor role to specifically control the robust rise in Th17 inflammation during late stages of infection.
Phenotypic analysis of the Th17-like Tregs revealed high frequencies expressing cytokines and trafficking markers similar to that of Th17. However, the abundance of Th17-like Treg expressing regulatory markers such as CTLA-4, OX-40 and PD-1, resemble a Treg profile. Furthermore, Th17-like Tregs express the thymic-derived nTreg marker, Helios, and were detected in the lungs during late infection but not in the blood or thymus, which suggests their derivation from lung nTregs. When IFNα was spiked into a Th17-polarized allogeneic assay, T-cell differentiation skewed towards Th17-like Tregs. In vitro functional analyses of these cells confirmed their suppressive nature. These data imply that there is a balance between IFNα Treg-favoring conditions and a Th17-polarizing environment that push Tregs to a Th17-like state during Bp infection.
This study contributes valuable information about adaptive IL-17 responses that are crucial to the resolution of whooping cough.
Sirt1 decreases TLR2-mediated Mac-1 expression in atherosclerosis
Authors: LEE SEUNG-JIN , KIM CHI DAE 
Published: January 2023

Abstract
Sirtuin (Sirt) 1 has been demonstrated to exerts protective effects in the progression of atherosclerosis, however, the underlying mechanisms are unclear. Thus, this study investigated the the role of Sirt1 in TLR2-mediated monocyte adhesion to vascular endothelium, which is a key early event in macrophage foam cell formation. The atherosclerotic lesion formation in aortic sinus was significantly increased in Pam3CSK4-treated wild type (WT) mice, which was significantly inhibited in Sirt1 Tg mice group. An en face immunohistochemistry of endothelial surfaces revealed a marked increase in monocyte adhesion to aortic endothelium in WT mice treated with Pam3CSK4, which was significantly attenuated in Sirt1 Tg mice. Likewise, the adhesion capacity of primary monocytes isolated from Pam3CSK4-treated WT mice was higher than those of monocytes from Sirt1 Tg mice. In in vitro study, Pam3CSK4 increased monocyte adhesion to endothelial cells with an enhanced Mac-1 expression. These were attenuated by a recombinant Sirt1, as well as by molecular overexpression of Sirt1 in monocytes. In addition, we found that Pam3CSK4-reduced Sirt1 expression in monocytes was regulated by the transcription factors, NF-kB and CREB. The role of NF-kB and CREB in Pam3CSK4-reduced Sirt expression was confirmed by siRNA knockdown of Sp1 and NF-kB. Sirt1 supresses atherosclerosis progression by TLR2-mediated monocyte adhesion to endothelium through Mac-1 expression, which is mediated by NF-kB and CREB pathways in monocytes, consequently leading to the development of therapeutic interventions for regulating Sirt1 expression in atherosclerosis.
Role of oxidative stress in the suppression of immune responses in peripheral blood mononuclear cells exposed to combustible tobacco product preparations
Authors: Arimilli Subhashini , Damratoski Brad , Prasad G.L. 
Published: January 2023

Abstract
Cigarette smoking is a major risk factor for several human diseases. Chronic inflammation, resulting from increased oxidative stress, has been suggested as a mechanism that contributes to the increased susceptibility of smokers to cancer and microbial infections. We have previously shown that whole smoke-conditioned medium (WS-CM) and total particulate matter (TPM) prepared from Kentucky 3R4F reference cigarettes potently suppressed agonist-stimulated cytokine secretion and target cell killing in peripheral blood mononuclear cells (PBMCs) under ex vivo conditions. Here, we sought to investigate the role of oxidative stress from cigarette smoke exposure in the compromised immunity observed in smokers. Particularly, we investigated the mechanisms of WS-CM and TPM induced suppression of select cytokine secretions in TLR agonist-stimulated cells, and target cell killing by effector cells in PBMCs. Pre-treatment with N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established antioxidant, protected against DNA damage and cytotoxicity caused by exposure to WS-CM and TPM. Similarly, secretion of IFN-γ, TNF, IL-6 and IL-8 in response to TLR-4 stimulation was restored by NAC. Target cell killing, which is used as a functional measure of cytolytic cells in PBMCs, is suppressed by WS-CM. Pretreatment with NAC restored the target cell killing in WS-CM treated PBMCs. This was accompanied by higher perforin levels in the effector cell populations. Collectively, these data suggest that reducing oxidative stress caused by cigarette smoke components restores select immune responses in this ex vivo model.
Myeloid cell regulation by CD200 signalling in atherosclerosis
Authors: Kassiteridi Christina , Cole Jennifer , Goddard Michael , Green Patricia , Park Inhye , Danso-Abeam Dina , Monaco Claudia 
Published: January 2023

Abstract

Background
Atherosclerosis, the major risk factor for cardiovascular disease and the leading cause of death worldwide, is a multifactorial chronic inflammatory disease. Deletion of CD200 in vivo increases myeloid cell numbers and activation resulting in enhanced susceptibility to autoimmune diseases and infection. However, the importance of CD200 in atherosclerosis development is still unknown.

Methods and Results
To understand the role of CD200 signalling, both the effect of CD200 deletion and provision were assessed in a murine model of atherosclerosis. Firstly, CD200 deficiency in hypercholestorelemic apolipoprotein E deficient (ApoE−/−) mice accelerates advanced atherosclerotic lesion formation in the aortic roots. Moreover, APOE−/− CD200−/− mice exhibit significant increase in specific myeloid cell populations in spleen, blood and aorta. Secondly, the role of CD200R ligation has been examined in a murine model of carotid injury. ApoE−/− mice underwent surgery for placement of a perivascular collar and were treated with 10mg/kg of a CD200-Fc fusion protein. CD200-Fc fusion protein treatment attenuates neointima development and, interestingly, affects macrophage accumulation and polarization.

Conclusions
Our data indicate that CD200 is an important modulator of myeloid cell function and phenotype in atherosclerosis and suggest that targeting the CD200-CD200R pathway holds promise as a potential therapeutic strategy in atherosclerosis.
Prenatal methyl-donor supplemented diet increases endoplasmic reticulum stress and inflammation in adipose tissue CD11b+ cells in F1 mice
Authors: Mau Theresa , Ghosh Amiya , O’Brien Martin , Yung Raymond 
Published: January 2023

Abstract
The risk for development of metabolic and cardiovascular diseases in later life is increasing, as the population is becoming overweight and obese at earlier ages. Early-life nutritional programming influences late-life disease susceptibility across generations, in part through epigenetic mechanisms including DNA methylation. Using mouse models, it has been shown that prenatal diet rich in methyl donors (L-methionine, vitamin B-12, folic acid, choline, betaine, zinc) can increase airway reactivity but improves cardiovascular disease outcomes in F1 mice. Here, we used a prenatal diet enriched with methyl-donors to study the impact of the prenatal diet in the context of diet-induced obese F1 C57Bl/6 mice fed a 40% high-fat diet (HFD) for 16 weeks. F1 mice exposed to the prenatal methyl donor supplemented diet have increased number of adipose tissue ‘crown-like structures’ consisting of primarily CD11b+ cells. The prenatal diet was found to increase the expression of adipose tissue endoplasmic reticulum (ER) stress response genes Chop, Bip, and Atf4 in HFD F1 mice. Obesity-induced ER stress has been linked to adipose tissue chronic inflammation. We have previously established that ER stress contributes to aging adipose tissue macrophage inflammation. Interestingly, Mcp-1 and Tnfα gene expression were found to be increased in the CD11b+ cells of F1 mice adipose tissue. The results strongly support an important role of prenatal methyl-donors exposure in modulating diet-induced obesity ER stress response and inflammation in offspring.
Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization
Authors: Lagraauw Max , Wezel Anouk , van der Velden Daniel , Kuiper Johan , Bot Ilze 
Published: January 2023

Abstract
Mast cells accumulate in the perivascular tissue during plaque progression and upon activation release pro-inflammatory cytokines and extracellular matrix degrading enzymes which fuel the inflammatory process and decrease lesion stability. Interestingly, mast cells have been shown to co-localize with peripheral neurons and contain receptors for various hormones and neuropeptides which are released upon exposure to stress. Therefore, we hypothesize that stress-induced neuronal activation of mast cells contributes to plaque destabilization.
In apoE−/− mice the acute stress induced by 120′ restraint caused a significant increase in mast cell activation in the heart (37.3 ± 1.8% vs. 50.1 ± 4.9%). In parallel with a rise in serum corticosterone levels we observed a transient increase mast cell-specific β-hexosaminidase levels and the pro-inflammatory cytokine, interleukin-6 in the stressed mice compared to controls (55.9 ± 11.0 pg/ml vs. 29.6 ± 5.49 pg/ml). Subsequent characterization of atherosclerotic lesions in the aortic root revealed a significant reduction in lesion collagen content and a higher incidence of intraplaque hemorrhages, a hallmark of the vulnerable plaque (38.5% vs. 7.7%).
Importantly, both these effects were reduced in mice treated with the mast cell stabilizer cromolyn and completely abolished in mast cell deficient (apoE−/−/Kit(W-sh/W-sh)) mice, thus strongly indicating the involvement of a mast cell-dependent response to stress in atherosclerotic plaque destabilization.
We demonstrate that acute stress activates mast cells near atherosclerotic lesions and contributes to plaque destabilization, identifying acute stress as a risk factor for acute cardiovascular syndromes.