bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA miR-155 promotes medullary thymic epithelial cell maturity and regulatory T cell development
Authors: Dong Jiayi , Warner Lindsey , Chen Mei-Chi , Lin Ling-Li , Lu Li-Fan 
Published: January 2023

Abstract
MicroRNA-155 (miR-155) is a small non-coding RNA highly upregulated in regulatory T (Treg) cells, an immune cell population specialized in maintaining immunological tolerance. While the importance of miR-155 in conferring Treg cell competitive fitness has been well established, how miR-155 regulates Treg cell development remains unknown. By taking cell-type specific gene targeting approaches, we demonstrate that miR-155 controls thymic Treg (tTreg) cell differentiation in both T cell-intrinsic and -extrinsic manners. Specifically, we show that mature CD80hiMHCIIhi medullary thymic epithelial cells (mTECs) crucial for the generation of tTreg cells express high levels of miR-155, where TEC-specific deletion of miR-155 diminishes this population and impairs tTreg cell development. Previously, the size of the mature mTEC compartment has been shown to be regulated by TGF-β signaling. Here, our results identify SMAD3, a key molecule downstream of TGF-β signaling, is targeted by miR-155 in mTECs. Thus, we propose a miR-155-SMAD3-TGF-β axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tTreg cells.
Analysis of immune cells from mice with Chagas disease treated with NPOx-B
Authors: MANZANO OSCAR ARTURO ANGELES , Galicia Viridiana Galicia , Castro Ma Natividad Flores , Camacho Mitzi , Baeza Isabel , Wong Carlos , Wong-Baeza Carlos , Reséndiz-Mora Albany 
Published: January 2023

Abstract
Chagas disease is a parasitic disease caused by Trypanosoma cruzi it is endemic in Latin America, where is a major health problem since it affects 8–10 million people, causes 50,000 deaths per year and about 25% of the population is at risk of acquiring the disease. It remains practically incurable, mainly because of the limited interest in developing new drugs and because the drugs available for its treatment, Benznidazole (Bz) and Nifurtimox (Nx) are inefficient to cure patients. The acute phase of the disease appears shortly after infection, the chronic phase appears after a silent asymptomatic period that may last several years. During the chronic phase, the heart, esophagus, colon and PNS are irreversibly affected, patients usually die from heart failure. The chronic phase may be established by the evasion of the immune response by the parasite, secondly because Bz and Nx generate free radicals that can affect the cells of the immune system (CIS) which could favour the chronic phase. In our research group, we design and synthesized the benzyl ester of Npropyl oxamic (NPOxB) that is an effective inhibitor of the alpha-hydroxy acid dehydrogenase II enzyme, which is a specific enzyme in the glycolytic pathway of the parasite. In this work we treated with NPOxB or Bz infected mice with NINOA or INC5 strains, we evaluate the parasitaemia, the macrophages, B, T, plasma and dendritic cells. The NPOx-B decreased more the parasitaemia of both T. cruzi strains than the Bz. The mice infected and treated with Bz showed a decrease in B, T and plasma cells compared to the infected mice treated with NPOxB. So NPOxB is more effective in decrease the parasitaemia and lacks the toxicity of Bz, it doesn’t affect in CIS, the cure of the disease can be achieved more efficiently.
Multidimensional phenotypic immune profiling of Chlamydia trachomatis infected women using mass cytometry platform.
Authors: Kollipara Avinash , Iannone Marie A. , Poston Taylor , Lee De’Ashia E. , O’Connell Catherine , Zheng Xiaojing , Hillier Sharon , Wiesenfeld Harold , Darville Toni 
Published: January 2023

Abstract
Chlamydia trachomatis (CT) is the most frequently reported bacterial sexually transmitted infection in the U.S., with 1 in 20 sexually active young women being infected. Infections are easily curable with antibiotics, but reinfections are frequent and infection can lead to reproductive tract sequelae. Adaptive immune responses generated during infection likely limit extent of infection, but frequently fail to prevent reinfection. We developed a 35 marker CyTOF panel to phenotype PBMCs. We examined PBMCs from women infected with CT alone (N=8), women with CT co-infected with gonorrhea or Mycoplasma genitalium (N=6), and from these same women 1 month post antibiotic treatment, and compared them to 11 healthy uninfected women. Compared to uninfected women, the frequency of B cells was increased in CT-infected women and remained elevated at 1 month, with no effects observed on various B cell subsets. Among T cells, Th1 and Tc1 percentages were reduced in CT-infected women and remained low at 1 month. Th2 and Th17 phenotype percentages were not different than uninfected women. Th1/Th2/Th17 cells expressing CD107a were reduced in CT-infected women, but rebounded towards normal at 1 month. Myeloid DCs were reduced in CT-infected women, but rebounded towards normal at 1 month. All of these differences were present regardless of coinfection. CD107a+ NK cells were reduced in CT-only infected women and failed to rebound at one month. The reductions in these various cell types is likely due to their trafficking to the infected tissue. CyTOF analysis of PBMCs from additional patients and of endometrial biopsy samples from these same subjects should provide important data related to the female host response to CT.
Loss of acid ceramidase activity in a murine model of Farber disease leads to an early and profound immuno-phenotype that reflects alterations in both the innate and adaptive immune cell populations
Authors: Coquery Christine Morel , Sampey Brante , Solyom Alexander , Gaukel Eric J. , He Xingxuan , Zhu Changzhi , DeAngelis Victor , Schuchman Edward H. , Wring Stephen A. 
Published: January 2023

Abstract
Farber disease is an ultra-rare lysosomal storage disorder where a deficiency of acid ceramidase activity leads to the accumulation of ceramide and the formation of granulomas which, in conjunction with a chronic inflammatory state, likely results in tissue damage. A rapidly progressive murine knock-in Asah1P361R/P361R model of Farber disease recapitulates many aspects of the human disease, including an increase in ceramide and pronounced tissue inflammation. The focus of this study was to describe the aberrant immune cells in this disease model. Blood, livers, lungs, and spleens were collected from 4- to 8-week old litter-matched Farber and wild-type mice for characterization by flow cytometry. Characterization of the monocyte population revealed a marked increase in the frequency of MHCII−CD11bhiLy6C+ cells (3–6 fold vs WT). These cells were highly activated as evidenced by CD86 expression, and skewed toward a pro-inflammatory M1 phenotype, based on CD38 expression. A concurrent decrease in CD206+ anti-inflammatory M2 macrophages was identified. In addition to the macrophage compartment, a profound increase in neutrophils in the spleen, liver, and lung was evident by 4 weeks of age (2–7 fold vs. wild-type). Marked differences in the adaptive immune compartment also were noted, with a clear increase in the frequency of plasmablasts (precursors to immunoglobulin-producing plasma cells), likely secondary to the increase in pro-inflammatory monocytes. Importantly, the alterations observed in the tissues were reflected in the blood of Farber mice. In summary, these data expand the characterization of the murine Farber disease model and provide insight into the immuno-phenotype of Farber disease.
Gain-of-function STING mutations induce T cell death in the SAVI mouse
Authors: Wu Jianjun , YAN NAN 
Published: January 2023

Abstract
STING is ER-localized protein that plays a central role in the innate immune response to microbial DNA, cyclic di-nucleotide and aberrant host DNA. We previously established a STING-associated vasculopathy with onset in infancy (SAVI) mouse model by introducing the N153S mutation in the mouse STING (N154S in the human STING). The SAVI mouse recapitulates several abnormal phenotypes observed in human patients, including inflammatory lung disease, T cell cytopenia and premature death; and these disease phenotypes surprisingly occur independent of IRF3. To further investigate the SAVI disease mechanism, we focused on the role of STING in T cell survival. We found that both mature CD4 and CD8 T cells in STING N153S mice are undergoing apoptosis. Inducible expression of STING N154S but not WT STING in Jurkat T cells also caused robust apoptotic cell death. Mechanistically, we defined a novel structural motif in the STING protein as well as an IFN-independent signaling cascade that are required for STING gain-of-function mutants to drive T cell death. We hope that genetic or pharmacological targeting of the STING-mediated cell death signaling pathway would be therapeutically useful for treating SAVI patients.
Extracellular ASC in bronchoalveolar lavage (BAL) fluid exists primarily in the soluble form and not in a speck complex
Authors: McAndrew Christian C. , Tsai MuChun , Napolitano Nina M. , Song Min-Ae , Shields Peter G. , Gavrilin Mikhail A. , Wewers Mark D. 
Published: January 2023

Abstract

Rationale
Apoptosis-associated speck-like protein containing a CARD (ASC) serves as an adaptor to link NOD-like receptors to caspase-1 during inflammasome activation. The oligomerization of ASC into a large speck-like complex appears to be crucial to this process. Furthermore, extracellular ASC specks may propagate an inflammatory response. Although extremely high levels of ASC exist in BALF, little is known about whether BALF ASC exists in the soluble form or as part of a speck complex.

Methods
Subjects (normal volunteers and patients with pneumonia) underwent IRB approved BAL. BALF was removed from cells by centrifugation at 400g and ASC was quantified by ELISA. Additionally, BALF was spun at 16,000g to pellet ASC specks and separate them from soluble ASC. Samples were crosslinked with DSS, separated on a denaturing gel, and immunoblotted with an anti-ASC antibody to visualize ASC oligomers.

Results
Extracellular levels of ASC were very high in the BALF when measured by ELISA and immunoblot. However, although pelletable ASC oligomers could easily be observed in stimulated THP-1 cell supernatants, no oligomers of ASC were found in BALF samples from healthy donors or pneumonia patients, and negligible amounts of ASC pelleted down when BALF was spun at high speed.

Conclusion
In contrast to inflammasome activated THP-1 cells, extracellular ASC in BALF exists primarily in the soluble non-oligomeric state. This observation held true for healthy donors and donors with lung infections.
Observed increases in CD4:CD8 and TIGIT expression during sofosbuvir-based therapy in a longitudinal hepatitis C cohort
Authors: Stevenson Timothy J. , McMahon Brian , Townshend-Bulson Lisa , Hewitt Annette , Barbour Youssef , Espera Hannah , Homan Chriss , Varney Danielle , Gove Jim , Rhodes Wileina , Snowball Mary , Otto Evon , Plotnik Julia , Negus Susan , Simons-Petrusa Brenna 
Published: January 2023

Abstract
Chronic hepatitis C virus (HCV) infection reduces immune function through exhaustion and repertoire reduction. Sofosbuvir-based direct-acting antiviral (DAA) therapies offer &gt;90% sustained virologic response (SVR) for HCV infection, but the extent of immune recovery and relationship with clinical factors are unknown. The longitudinal Alaska Hepatitis C Cohort provides an opportunity to evaluate immune recovery following sofosbuvir-based DAA and determine the influence of an extensive clinical and laboratory history. Forty-two persons (genotype 1; mean age 50 ± 12 years; 69% female) received 8 or 12-week sofosbuvir-based DAA therapy. Mean HCV RNA detection date was 2007 (range: 1994–2017). Pre-treatment HCV RNA levels averaged 4.9×106 IU/L (range: 4.9×104–2.4×107), were not detectable in any person after 4-weeks of therapy, and all achieved SVR. 18% (n=7) of persons had a fibrosis score of ≥F2 (moderate fibrosis to cirrhosis). Peripheral blood mononuclear cells (PBMCs) were evaluated at four time points: Pre-treatment (Pre), 4-weeks treatment (4wk), End of Treatment (EOT), and SVR post 12-weeks EOT (SVR-12) by flow cytometry to evaluate memory, exhaustion, and functional immune markers. Initial analysis revealed a significant increase in the CD4:CD8 from 4wk to EOT (p=0.007). Regulatory T-cells significantly increased at EOT and SVR-12 compared to 4wk (p=0.04 and 0.03, respectively). TIGIT showed a significant increasing trend in T-cells and NK cells throughout sampling timeline. Preliminary analysis indicates sofosbuvir-based DAA supports immune recovery to some extent. Additional analysis of immune recovery markers, determination of estimated date of HCV infection, and correlation of morbidity factors continues.
Sex differences in Vitamin D alter inflammation during heart disease
Authors: Bruno Katelyn A. , Mathews Jessica , Douglass Erika , Hill Anneliese , Cooper Leslie T. , Hoyne Jonathan , Fairweather DeLisa 
Published: January 2023

Abstract
An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D (VitD). Considerable evidence indicates that VitD deficiency is associated with an increased risk of autoimmune and cardiovascular disease (CVD), yet it remains unclear whether low VitD is simply a biomarker or has a true pathologic role. In this study we examined how sex differences in VitD influences various CVDs. We found that patients with CVD had significantly lower VitD than healthy controls (no ICD9/10 codes) (p=4E-6). In myocarditis patients low VitD correlated to poor ejection fraction (EF) in women with myocarditis (p=0.02), but high VitD correlated with low EF in men (p=0.04). In VDR knockout mice we found that VDR decreased myocarditis in females (p=2E-8) but increased inflammation in males (p=0.03) with an increase in total immune cells (p=0.02), CD3, CD4 and CD8 T cells (p=0.04), and the inflammasome in females. VDR altered Treg (p=0.04), mast cells (p=0.04) and cytokine profiles in males. Additionally, sera VitD levels were significantly higher in WT male mice with myocarditis compared to females. Our findings in VDR mice indicate that VitD/VDR reduces myocarditis in females, but increases disease in males. These data suggest that VitD sufficiency may increase inflammation in men, while VitD deficiency may make disease worse in women. These findings suggest that Vitamin D may have a role in the pathogenesis of inflammatory and cardiovascular disease.
Prevention of myocarditis using regenerative medicine therapy
Authors: Fairweather DeLisa , Bruno Katelyn A. , Hill Anneliese , Stalboerger Paul G. , Cooper Leslie T. , Behfar Atta 
Published: January 2023

Abstract
Myocarditis is an important cause of acute and chronic heart failure. We wanted to determine whether purified exosome product (PEP) can improve and/or prevent myocarditis using a preclinical mouse model of myocarditis. Because estrogen protects women from myocarditis and heart failure we also tested premenopausal PEP (pmPEP). To determine the appropriate dose of PEP/pmPEP, we administered PEP and pmPEP vs. PBS controls ip to male BALB/c mice at day −1, 0 and +1 after viral infection to induce myocarditis and harvested mice at day 10 post infection (pi) during the peak of acute myocarditis. We found that the dose and exposure route was successful. We found that pmPEP, but not PEP, significantly decreased acute myocarditis based on histology (ANOVA p=0.0009). and decreased total immune cells (CD45 p=0.008), macrophages, neutrophils and mast cells (CD11b p=0.04), macrophages (F4/80 p=0.009), and T cells (CD3 p=0.02, CD4 p=0.01) but no other immune cell populations in the heart. Markers for both M1 and M2 macrophages were also significantly decreased with pmPEP treatment, indicating a “global” decrease in inflammation. Importantly, CR1, the central inhibitor of the complement cascade, was significantly increased by pmPEP but not PEP (p=0.004). Next we treated male BALB/c mice with PEP, pmPEP or PBS ip on day 8, 9 and 10 pi (a clinically relevant timepoint) and harvested on day 11 pi during acute myocarditis. Here we found that both PEP and pmPEP significantly reduced acute myocarditis compared to controls (ANOVA PEP p=0.006, pmPEP p= 0.005). These findings suggest that PEP/pmPEP could be given to patients who come in with acute onset myocarditis to decrease the severity of disease and potentially prevent sudden death.
Anti-inflammatory miR-146a is protective against diet-induced obesity and regulates macrophage metabolism
Authors: Nelson Morgan , Runtsch Marah Clarice , O’Connell Ryan 
Published: January 2023

Abstract
MicroRNAs (miRNAs) have been recognized for their ability to regulate many aspects of mammalian immunity. miR-146a is one such miRNA that restricts inflammation by dampening pro-inflammatory signaling pathways. Here we investigate the role of miR-146a in protecting against diet-induced obesity (DIO), an inflammatory and metabolic disease that affects one-third of adults in the United States and increases risk for developing other health-related diseases. In this study, we placed miR-146a−/− and WT mice on a high-fat diet (HFD) or standard diet and observed significant weight gain, increased fat content, adipocyte hypertrophy, and increased serum glucose levels in miR-146a−/− mice compared to WT mice on HFD. Furthermore, we observed increased macrophage infiltration into adipose tissue and elevated inflammatory gene expression in metabolic tissues in the absence of miR-146a.
In WT mice, miR-146a expression was higher in adipose-resident immune cells than in adipocytes, prompting us to perform RNA-seq on adipose tissue macrophages (ATMs) from miR-146a−/− and WT mice. This revealed that in addition to regulating pro-inflammatory gene expression, miR-146a also regulates AKT activation and the metabolic capacity of macrophages through a mechanism involving its direct target Traf6. Overall, this work identifies a critical role for miR-146a in repressing DIO and associated metabolic and inflammatory symptoms, and suggests that miR-146a mimics may present an effective therapy to treat such conditions in the clinic. The future directions of this project include determining the cell intrinsic role of miR-146a in this disease phenotype and working out the mechanism whereby miR-146a regulates macrophage metabolism.
Obesity-driven IL-18 inhibits the suppressive function of FOXP3+ T-regulatory (Treg) cells
Authors: Akimova Tatiana , Zhang Tianyi , Beier Ulf H. , Jiao Jing , Diamond Joshua M. , Christie Jason D. , Simmons Rebecca A. , Hancock Wayne W. 
Published: January 2023

Abstract
We investigated ways by which obesity affects the immune system and promotes inflammation, given that obesity has a high economic and medical impact, worldwide. IL-18 was the only inflammatory marker differing between our colonies of “obese but otherwise healthy” (hHFD) and “obese with low-grade inflammation” (iHFD) mice. All mice gained weight equally, had signs of low-grade inflammation (increased TNF-a, IL-1b and IL-6 mRNA) in adipose tissues, and high plasma leptin levels. The livers of hHFD mice had no inflammatory phenotype despite evidence of steatosis, whereas livers of iHFD mice had increased TNF-a, IL-1b, IL-6 and IL-7 mRNA. Levels of IL-18 were increased in livers and fat of iHFD, but not hHFD mice, and were associated with significant impairment of Treg suppressive function. Addition of IL-18 had significant inhibitory effects on the suppressive function of murine and human Tregs, and Tregs isolated from obese/overweight patients also had impaired suppressive activity. Human Tregs express high levels of IL-18Ra, and downregulate FOXP3 protein but not mRNA, when stimulated in the presence of IL-18. FOXP3 downregulation compromises the FOXP3-regulated gene network, leading to re-activation of pro-inflammatory genes such as IFN-g, IL-2, IL-6 and IL-17, and downregulation of CTLA-4 protein, which is critical for suppressive function. Our preliminary data indicate that IL-18 activates the MyD88 pathway in Tregs and impairs FOXP3 protein stability, possibly by ubiquitination and proteasomal degradation. This may be a physiologically essential tool to dampen Treg function during acute infection and increase the efficiency of immune responses, but has a detrimental effect in obesity-driven low-grade inflammation.
Antioxidant treatment ameliorates cigarette smoke and respiratory syncytial virus-induced inflammatory response by blocking HMGB1 release
Authors: Hosakote Yashoda Madaiah , Rayavara Kempaiah , Hallberg Lance M. , Ameredes Bill T. , Kurosky Alexander 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants, and causes severe respiratory morbidity and mortality in the elderly. Second hand tobacco smoke is the major environmental risk factor for the development and severity of lower respiratory tract infections, however, the molecular mechanism of tobacco smoke-induced RSV severity is not fully understood. High mobility group box 1 protein (HMGB1) has been shown to functions in the regulation of cellular transcription and the activation of proinflammatory responses in many pathogenic conditions, but little is known about its molecular mechanism of action during its release in respiratory viral infections and tobacco smoke-induced lung inflammation. In this study we investigated the mechanism of HMGB1 release and associated cellular signaling in RSV and cigarette smoke (CS)-induced airway inflammation. A549 cells, a human lung carcinoma cell line and normal small alveolar epithelial (SAE) cells were pretreated with antioxidants and exposed to CS followed by RSV infection. CS exposure in combination with RSV infection synergistically enhanced HMGB1 secretion with concomitant decrease in the total cell lysates when compared to uninfected as well as each stimulus alone. NFκB and MAPK were significantly activated in CS exposed and RSV-infected cells. Treatment with antioxidant significantly inhibited RSV and CS-induced HMGB1 secretion, cytokine release, and NFκB and MAPK activation. The results of these studies will help to design new therapeutic strategies not only for RSV infection, but also for other respiratory diseases that have been shown to be caused or exacerbated by environmental toxicants such as tobacco smoke.