bluuebunny/crossref_metadata_2025_split huggingface dataset:
Th9-derived Interleukin-9 (IL-9) is a potential therapeutic target for inflammatory cardiovascular disease
Authors: BARAL ISHITA , Baumer Yvonne , Burma Aarohan , Falduto Guido , Sylvester McKella , Schwartz Daniella 
Published: November 2024

Abstract
Psoriasis is a systemic autoimmune disease with a global prevalence of 2-3% and is strongly associated with metabolic dysfunction, vascular inflammation, and atherosclerotic cardiovascular disease (CVD). The IL-23/IL-17 pathway is critical for psoriatic inflammation. However, IL23/IL-17 blockade has no effect on CVD outcomes. Hence, the potential drivers of psoriatic CVD are still to be elucidated. IL-9-producing PU.1+/CD3+/CD4+ Th9 cells are found in the skin and circulation of patients with psoriasis. We found a significant association of Th9 cells with early radiographic atherosclerotic coronary artery disease in a psoriatic patient cohort. We observed an increase in aortic plaque size, and skin/aortic Th9 cells in a psoriatic atherogenesis model (IMQ-treated ApoE KO mice). To understand the involvement of IL-9 as a driver of the disease, we pharmacologically inhibited IL-9 in different modified disease models. IL-9 blockade-treated mice showed decreased skin inflammation compared to isotype-treated mice, accompanied by reduced aortic plaque formation. In vitro, IL-9 induced endothelial cell dysfunction through STAT3. Together, these results suggest that Th9/IL-9 may be a therapeutic target to prevent psoriasis-related atherosclerotic CVD. To further support our finding, we developed IL-9RKO/ApoE KO mice model, as well as conditional deletion of IL9R in various cell types. Further, transcriptomic profiling of endothelial cells will elucidate upon IL-9/STAT3 targets.
A role of DRAK2 in regulatory T cell (Treg) survival and T cell metabolic reprogramming
Authors: Lee Sarah , Walsh Craig , Nguyen Madison , Zangenberg Emma 
Published: November 2024

Abstract
Multiple Sclerosis (MS), one of the prevalent autoimmune disorders causing damage to the brain and spinal cord, requires safer therapeutics since current therapies rely on general immunosuppression, rendering patients susceptible to infection. Prior studies revealed that DAP kinase-related apoptosis-inducing protein kinase 2 (DRAK2) KO mice exhibit resistance to EAE, a mouse model for MS. DRAK2 deficiency also induced an overall reduction in T cell proliferation but an increase in proportion of regulatory T cells (Tregs) upon in vitro stimulation, potentially due to metabolic shift in T cells. To investigate the impact of DRAK2 deficiency on the expansion of different T cell subsets and how it reshapes T cell metabolism, WT and DRAK2-/- mice were used to quantify different T cell subsets and inspect significant alterations in mitochondrial metabolism. Results demonstrated decreased effector T cells and lipid contents in DRAK2-/- mouse T cells upon stimulation. A DRAK2 deficiency displayed an increase in mitochondrial membrane potential using JC-1 and TMRE staining of mouse T cells. RNA sequencing of T cells in WT and DRAK2-/- mice revealed that the absence of DRAK2 promotes the expression of TRIM family proteins which are closely associated with cGAS-STING DNA sensing pathway presumably caused by mtDNA. Altogether, these findings support the hypothesis that DRAK2 serves as a key metabolic regulator in T cells, heightening its potential as a new therapeutic target for MS.
Antigen persistence following mRNA vaccination and the immune consequence of lymph node stromal cell delivery
Authors: Belfon Robert , Tamburini Beth , Hesselberth Jay , Lasda Erika 
Published: November 2024

Abstract
mRNA vaccines have demonstrated their usefulness on a global scale in recent years. They elicit potent humoral and cell mediated responses, but the specific mechanisms by which these responses are produced still require investigation. Our lab described a process termed antigen archiving, in which antigen is retained within lymph node stromal cell (LNSC) subsets following viral infection and subunit vaccination to bolster/prolong memory CD8 T cell responses. Whether mRNA vaccines utilize this mechanism to promote immunity has yet to be determined. Data suggest mRNA-derived antigen persists within LNSC of C57/BL6 mice for at least 3 wks following subcutaneous or intramuscular delivery. We investigate the immune consequence of this prolonged antigen retention using ionizable lipid nanoparticles (LNP) to deliver mRNA constructs encoding the model antigen ovalbumin as well as a fluorescent siinfekl-GFP to monitor antigen-specific T-cell responses and localization of antigen within murine lymph nodes (LNs). We identified LNP formulations facilitating differential uptake/translation within LNSC which also demonstrated robust antigen-specific CD8 T cell responses and persistence of antigen presentation within LNs for at least 3 wks in vivo. We plan to interrogate the immune consequences of enhanced stromal cell targeting and subsequent antigen retention following mRNA vaccination. A better understanding of mRNA and protein delivery and retention will inform future vaccine design.
MicroRNA-29 regulates IgE class-switching in B cells and susceptibility to skin inflammation
Authors: Borbet Timothy , Hines Marcus , Boehringer Thomas , Morrison Tate , Gonzalez Sandra , Koralov Sergei 
Published: November 2024

Abstract
MicroRNA (miRNA) gene regulation is vital for the development of B cells. Our group established that the miR-29 family is a regulator of B cell survival and B cell receptor (BCR) signaling. Specifically, we identified PTEN as a direct target of miR-29. Conditional knockout of miR-29 in B cells diminishes cell viability, which is compensated by normalizing Pten expression. In our latest observations, mice with a B-cell-specific miR-29 deletion exhibited an inflammatory skin phenotype, characterized by cutaneous lesions, continuous itching and a 50% survival rate. Pten ablation fails to improve their lifespan. These findings indicate that miR-29 targets other transcripts in B cells apart from Pten. Notable features such as epidermal proliferation and elevated serum IgE levels. We hypothesize the absence of miR-29 in B cells may lead to to atopic dermatitis. Computational analysis predicts miR-29 likely regulates Il4Ra transcript levels, and qPCR supports this prediction. Our in vitro assays demonstrate that B cells deficient in miR-29 exhibit greater IgE class switching when stimulated with IL-4, compared to wild-type counterparts. Additionally, we observed that mice developing inflammatory skin conditions harbor an increased Staphylococcus burden. Therefore, we propose that miR-29 plays a role in the co-regulation of Pten and Il4ra to influence the survival and function of mature B cells and may alter how these cells respond to environmental/microbial antigens.
The role of HLA-DQ8 and B cells on CD8 IEL activation in celiac disease pathogenesis
Authors: Voisine Jordan , Meyer Celine , Xiao Zhiping , Chun Angela , Davis Amelia , Esubalew Nebiyat , Kauffman Tierney , Jabri Bana , Abadie Valerie 
Published: November 2024

Abstract
Celiac disease (CeD) is an autoimmune-like inflammatory disorder of the small intestine that is triggered by dietary gluten and develops in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules. 1% of the worldwide population is affected by the disease. CeD is characterized by the loss of oral tolerance to gluten manifested by HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4 T cells in the small intestinal mucosa and by a massive expansion of cytotoxic intraepithelial CD8+ lymphocytes (IE-CTLs) that are involved in the killing of intestinal epithelial cells, resulting in villous atrophy (VA). Using the first transgenic CeD mouse model that recapitulates the major clinical features of CeD, including VA, we demonstrated that tissue destruction was dependent on IE-CTLs, HLA-DQ8 and B cells. To uncover the mechanisms enabling VA, we characterized IE-CTL activation during CeD development and identified a particular CD8ɑβ IEL subset that becomes activated and highly cytotoxic in a gluten and HLA-DQ8-dependant manner. Strikingly, HLA-DQ8-expressing B cells acted as antigen-presenting cells for gluten peptides and drove the sustained activation of cytotoxic CD8ɑβ IE-CTLs. Our results support a critical role of B cell-T cell interactions for CeD pathogenesis and suggest that the expression of HLA-DQ8 on B cells is required to promote cytotoxic CD8abintraepithelial lymphocyte activation and the ensuing tissue destruction in CeD.
Identification of T regulatory cell (Treg) proliferation induced by IgM+IgDlo regulatory B cell (BDL) using a multi-color immunofluorescence strategy
Authors: Beltrame Angela , Dittel Bonnie 
Published: November 2024

Abstract
Multiple sclerosis is an autoimmune disease driven by T cell orchestrated demyelination. CD4+Foxp3+ T regulatory cells (Treg) suppress autoimmunity; thus, therapies to increase endogenous Treg numbers are ideal. We identified a novel subset of regulatory IgM+IgDlow/- B cells (BDL) that induce Treg proliferation in a glucocorticoid-induced TNFR-related ligand (GITRL)-dependent manner via cell-cell contact. However, where BDL localize with Treg in the spleen is unknown and imaging is challenging due to numerous required markers. Because Treg are located in the T cell zone, we hypothesize BDL migrate to and interact with Treg at the T-B boundary. A multi-color panel was developed to visualize, localize, and quantitate BDL-Treg conjugates. Fluorescent antibodies were selected via compensation methods using single-stained controls. Serial splenic sections were used to localize BDL-Treg interactions by staining a section with antibodies for splenic architecture: MAdCAM-1 (marginal zone), IgM (B follicle), and CD4 (T cell zone). The consecutive section was stained with antibodies to identify BDL (IgM, IgD), Treg (CD4, Foxp3), and proliferation (Ki-67). This strategy successfully identified Ki-67+ Treg-BDL conjugates in the T-B boundary. Future studies will quantitate the number of Ki-67+ Treg surrounded by BDL. We hope this strategy can be used to aid the development of a BDL-based therapeutic to increase endogenous Treg numbers and reduce autoimmunity.
B-1 cells contribute to plasma cell accumulation in Lyn-/- mice
Authors: Satterthwaite Anne , Ottens Kristina , Schneider Jalyn 
Published: November 2024

Abstract
The autoimmune disease systemic lupus erythematous is characterized by the production of pathogenic autoantibodies that drive inflammation and tissue damage. Defining which B cell subsets give rise to these autoantibodies may reveal therapeutic strategies that target pathogenic B cells while sparing responses to immunization and infection. Mice lacking the tyrosine kinase Lyn develop lupus-like autoimmune disease and accumulate autoreactive plasma cells in the spleen. We hypothesized that preventing plasma cell formation in Lyn-/- mice would result in an accumulation of cells that would have otherwise terminally differentiated. Deleting IRF4, a transcription factor required for plasma cell differentiation, from Lyn-/- mice resulted in a dramatic increase in B-1 cells in the peritoneal cavity and the spleen. B-1 cells are an innate-like subset of B cells that produces natural antibody and has been suggested to play both protective and pathogenic roles in autoimmune and inflammatory disease. A B-1 cell cre-reporter labeled about half of the splenic plasma cells in Lyn-/- mice, suggesting that B-1 cells may contribute to autoantibody production in this lupus model. Ongoing studies are aimed at determining the degree of autoreactivity of these labeled plasma cells in comparison to that of the B-1 cells that accumulate in Lyn-/-IRF4-/- mice.
The Crucial Role of A20 in Human B Cell Function: Implications for Immunoregulation and Autoimmunity
Authors: Sutton Rachel , Gupta Mansi , Scharer Christopher 
Published: November 2024

Abstract
Autoimmune diseases, such as systemic lupus erythematosus (SLE), are underscored by dysregulated B cell function including the production of autoantibodies, skewed population ratios, and aberrant signaling. Given that the family of nuclear factor kappa B (NF-kB) transcription factors govern responses to stimuli, survival, differentiation, and so forth understanding the intricate regulatory network of NF-kB in B cell biology is paramount for unraveling treatments for B cell-linked autoimmune diseases. Here, we focus on a negative regulator of NF-kB signaling, A20 (TNFAIP3), that deactivates NF-kB transcription factor translocation through the ubiquitination and deubiquitination of target proteins. Haploinsufficiency in A20 results in an autoimmune phenotype and mutations to A20 have been associated with SLE, suggesting implications to B cell function. To investigate the role of A20 in B cell signaling, we generated a TNFAIP3 knockout (KO) human B cell line. We then stimulated KO and WT cells with agonists such as B-cell activating factor (BAFF), CD40L, anti-IgM, TNFa, and R848 that activated distinct modes of NF-kB signaling. Using a combination of qRT-PCR, western blotting, and flow cytometry, the differences in gene expression patterns, protein production, and activation of NF-kB transcription factors were evaluated. Together, these findings provide a framework to understand how A20 controls B cell signaling and contributes to B cell-regulated autoimmune diseases.
Identification of environmental factors that promote intestinal inflammation
Authors: Kenison-White Jessica , Sanmarco Liliana , Chao Chun-Cheih , Wang Yu-Chao , Li Zhaorong , Rone Joseph , Quintana Francisco 
Published: November 2024

Abstract
Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)—a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. To overcome this limitation, we developed an integrated systems approach which combines publicly available databases, zebrafish chemical screens, machine learning, and mouse preclinical models to identify environmental factors that control intestinal inflammation. Using this approach we established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we found that an AHR–NF-κB–C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.
Comparative transcriptomic analyses of in vivo-differentiated alveolar macrophages reveals unique as well as differential gene signatures and biological pathways
Authors: Vo Thao , Singamsetty Dhruthi , Lamichhance Richa , Saini Yogesh 
Published: November 2024

Abstract
Alveolar macrophages (AMs) originate from fetal liver and self-renew under homeostasis. However, exposure to environmental agents is known to alter alveolar macrophage populations by promoting self-renewal and/or by inducing recruitment and differentiation of bone marrow-derived circulating monocytes. However, the transcriptomic profiling of fetal- versus bone marrow-derived AMs populations remains awaited. Therefore, we conducted transcriptomic analysis on two in vitro-differentiated (bone marrow-derived macrophages (BMDMs) and fetal liver-derived macrophages (FLDMs)) and three alveolar macrophage (BM-chimera, FL-chimera and naive C57BL6/J mice) populations. We hypothesized that, due to their fetal-liver origin, FLDMs, FL-chimera and naïve alveolar macrophages exhibit comparable gene expression patterns. Interestingly, the Principal Component Analysis revealed separation of these three macrophage populations, suggesting that lung microenvironment as well as precursor origin are critical in shaping AM gene expression profile. This finding was further supported by differential gene expression analysis. Custom gene sets relevant to selective macrophage functions revealed distinct expression patterns in in vitro, naïve, and chimeric AMs. This study is likely to provide critical insights on how lung microenvironment and precursor origin define gene expression and associated biological pathways.
Exploring the Immunomodulatory Potential of Natures Immuno: A Study on Mushroom Formulations in Alleviating LPS-Induced Inflammation.
Authors: Nascimento Amanda , Pandher Upkar , Thompson Brooke , Schneberger David , Singh Baljit , Kirychuk Shelley 
Published: November 2024

Abstract
Introduction: Inflammatory diseases, such as pulmonary inflammation, lung cancer, and asthma, pose a significant global economic impact, affecting health and quality of life. Proinflammatory cytokines released by the immune system can be activated by Lipopolysaccharides (LPS), an endotoxin mimicking infection by Gram-negative bacteria. Literature suggests an increased risk of inflammatory diseases in females compared to males. Natures Immuno, a formulation extracted from five commonly used mushrooms (Turkey Tail, Cordyceps, Reishi, Shiitake, and Agaricus), aims to address this issue. However, the combined influence of these mushrooms on the immune system is poorly understood. To explore this, we conducted a series of studies evaluating the effect of the treating with this formulation on LPS-induced inflammation. Methods: C57Bl/6 male and female mice (n = 7 per group) were challenged with or without LPS. After the challenge, they were divided into eight groups. Four groups received 1 drop of Natures Immuno twice daily for 5 days, while four groups acted as a control. Inflammatory differences were compared in blood, bronchoalveolar lavage fluid, and lung tissue samples at the end of the treatment periods. Results: Lung inflammatory markers in Natures Immuno-treated mice were significantly lower than in LPS-treated mice. Conclusions: These findings suggest that treatment with these five mushrooms may assist in supporting the immune system against LPS-induced inflammation.
IL-10 differentially promotes mast cell responsiveness to IL-33 resulting in induction of anaphylaxis and suppression of neutrophilia
Authors: Ranjitkar Saurav , Krajewski Dylan , Garcia Chelsea , Polukort Stephanie , Rovatti Jeffrey , Mire Mohamed , Tedeschi Caitlin , Blesso Christopher , Jellison Evan , Schneider Sallie , Ryan John , Mathias Clinton 
Published: November 2024

Abstract
Mast cells (MCs) play critical roles in the establishment of allergic diseases. We recently demonstrated an unexpected, proinflammatory role for IL-10 in regulating MC responses. IL-10 enhanced MC activation and promoted IgE-dependent responses during food allergy. However, whether the effects of IL-10 on MCs extend to IgE-independent stimuli is not clear. Herein, we demonstrate that IL-10 plays a critical role in driving IL-33-mediated MC responses. IL-10 stimulation significantly enhanced MC expansion, ST2 expression, IL-6 and IL-13 production, and MC degranulation in IL-33-treated BMMCs. In contrast, it suppressed TNF-a in IL-33-responding cells. These differential effects also extended in vivo. In a model of IL-33-induced neutrophilia, IL-10 enhanced IL-33 responsiveness leading to increased MC activation and suppression of neutrophils via decreased TNF-a. In contrast, during IL-33-induced type 2 inflammation, IL-10 priming exacerbated MC activity, resulting in MC recruitment to various tissues, enhanced ST2 expression and induction of anaphylaxis. Our data elucidate a novel role for IL-10 as an augmenter of IL-33-mediated MC responses, with implications during both allergic diseases and other MC-dependent disorders.
NLRP12 negatively regulates alcohol-induced fatty liver disease
Authors: Alam Manzar , Zaki Hasan 
Published: November 2024

Abstract
Alcoholic liver disease (ALD) characterized by hepatic steatosis, fibrosis, and inflammation is a global health problem caused by chronic consumption of alcohol. NOD-like receptor family member NLRP12 has emerged as a negative regulator of inflammation in diverse pathophysiological conditions. We previously showed that Nlrp12 deficiency promotes hepatocellular carcinoma (HCC) in mice and increased HCC was associated with higher hepatic steatosis and inflammation. However, the role of NLRP12 in alcohol-induced liver disorder was unknown. Here we investigated the role of NLRP12 in ALD using mouse models and in vitro studies. WT and Nlrp12-/- mice were fed with an alcohol diet for 4 weeks. Histopathological analysis showed increased steatosis in Nlrp12-/- mouse livers. Consistently, there was higher expression of proinflammatory cytokines and chemokines, and activation of JNK and AKT pathways as measured by real-time PCR and Western blotting, respectively. To understand the role of NLRP12 in alcohol-induced steatosis and inflammation, we stimulated primary hepatocytes from wild-type and Nlrp12-/- mice with ethanol. Interestingly, inflammatory responses as well as activation of JNK and AKT were higher in alcohol-treated Nlrp12-/- hepatocytes compared to those of wild-type. Similar responses were also seen in Nlrp12-/- macrophages stimulated with alcohol. Together these data suggest that NLRP12 is a critical negative regulator of alcohol induced liver disorders.
Peripherally activated brain CD8+ T cells promote AD in 5xFAD mice
Authors: Biragyn Arya , Campbell Britney , Bodogai Monica , Wang Xin , McDevitt Ross , Konda Kumaraswami 
Published: November 2024

Abstract
The role of the adaptive immunity in Alzheimer’s Disease (AD) remains poorly understood. Recent findings from our group, which link B cells to manifestation AD 1, and others, which show increase of CD8+ T cells in the AD brain 2, suggest that the adaptive immunity is an important but overlooked player in this progressive neurodegenerative disease. Here, our aim was to determine the role of CD8+ T cells in the brain in transgenic 5xFAD mice, which develop human AD-like symptoms. We manipulated brain CD8+ T cells in AD mice by depleting circulating CD8+ T cells with anti-CD8 mAb or expanding antigen-specific CD8+ T cells with Aβ-CoreS (encodes Ab1-11) RNA immunization. We found that while the CD8+ T cell depletion decreases Aβ plaques and disease-associated microglia in the hippocampus, and improves cognition, Aβ-CoreS exacerbates AD symptoms via increasing brain CD8+ T cells with cytotoxic and exhausted phenotype. Overall, our results indicate the AD manifestation requires brain antigen-specific CD8+ T cells, which upon peripheral induction/expansion infiltrate the brain and exacerbate AD symptoms. We propose that CD8+ T cells may similarly exacerbate AD in humans, as we detected their significant increase in the brain of deceased people with AD.
1. Kim et al. Nat Commun. 2021;12(1):2185.
2. Gate et al. (2020). Nature 577, 399-404.
This research was supported by the Intramural Research Program of the National Institute on Aging, NIH