bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular retinoic acid binding protein 2 (CRABP2) serves as a critical regulator in immune regulation and inflammation
Authors: Takazawa Ikuo , Larange Alexandre , Cheroutre Hilde 
Published: January 2023

Abstract
Retinoic acid (RA) is a metabolite of Vitamin A, which plays anti-inflammatory roles by ligating and transactivating nuclear RA receptors that control gene expression and cell differentiation. Cellular retinoic acid binding protein 2 (CRABP2) binds to and transports RA from the cytoplasm to the nucleus. Because of its direct interaction with RARs bound to retinoic acid responsive elements (RARE) in the promoters of RA target genes, CRABP2 specifically channels RA to chromatin-bound nuclear receptors, which then mediate transcriptional activation and expression of RA target genes. CRABP2 is not expressed in naïve T cells, but strongly induced in response to T cell receptor (TCR) signaling. Consequently, activated T cells from CRABP2 KO animals show reduced RARE-luciferase reporter activity, indicating that TCR-induced CRABP2 controls gene transcription and expression in activated T cells. In CD4 T cells we showed before that RA promotes the generation of Foxp3 Tregs and reciprocally suppresses the generation of Th17 cells. Consistent with that, CRABP2 KO mice show a marked reduction of Tregs in the periphery. In the absence of RA, CRABP2 remains in the cytoplasm where it functions in a non-genomic fashion and enhances expression of inflammatory cytokines. In biopsies from patients with various autoimmune diseases, inflammatory CD4 T cells with enhanced expression of CRABP2 accumulate whereas expression of RA target gene is reduced. These findings point at genomic versus non-genomic CRABP2 as an important regulator of the reciprocal generation of Tregs versus inflammatory Th17 cells. Defects in the regulation by activation-induced CRABP2 may form an important underlying cause in autoimmune and other inflammatory diseases.
IL-1β regulates IL-33 mediated T helper 2 (Th2)-biased immunopathophysiology following respiratory syncytial virus infection in an age-dependent and caspase-1 independent manner
Authors: Vu Luan D. , Siefker David T , You Dahui , DeVincenzo John P. , Phan Anh TQ. , Cormier Stephania A. 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) infection in children is a substantial clinical and health economic burden worldwide. RSV-induced immunopathophysiology has been related to age-variable IL-33 mediated Th2-biased immune responses. However, the mechanisms of the age-dependent regulation of IL-33 remain unclear. Here, we show for the first time that elevated levels of IL-33 in nasal aspirates from RSV infected human infants are associated with the disease severity. We further demonstrate the correlation of IL-33 levels with IL-1β in RSV-infected infants. IL-1β has been shown to induce expression of IL-33 in lung cells. Indeed, we found that intranasal treatment of neonatal mice with IL-1β prior to RSV infection significantly boosted the production of pulmonary IL-33. IL-33 increases coincided with an increased frequency of pulmonary type 2 innate lymphoid cells (ILC2) at 1 day post-infection (dpi) and Th2 biased immunopathophysiology after reinfection. Conversely, antagonizing IL-1β signaling in adult mice with IL-1βR antagonist (Anakinra) prior to RSV infection significantly enhanced IL-33 mediated Th2 biased immunopathophysiology after reinfection. Although it has been shown that IL-1β and IL-33 were regulated at the post-translational level by inflammasome-mediated caspase-1 activation, in our study active caspase-1 was detected exclusively within IL-33negCD45+ cells in RSV-infected lungs and was independent of age at infection. These findings suggest that IL-1β responses regulate RSV-induced IL-33 production via caspase-1 independent mechanisms in an age-dependent manner. More importantly, our findings provide the first data on respiratory IL-33 responses in RSV-infected infants.
Novel roles for the Ikaros zinc finger transcription factor Eos in regulating TH2 differentiation
Authors: Rasheed Mustafa N , Sreekumar Bharath , Moon Sol C , Powell Michael Duane , Read Kaitlin , Oestreich Kenneth J 
Published: January 2023

Abstract
CD4+ T cells differentiate in response to specific cytokine environments that induce the activation of STAT transcription factors and, ultimately, cell-specific gene profiles. The differentiation of TH2 cells requires the cytokines IL-4 and IL-2, which signal via the activation of STAT6 and STAT5, respectively. Interestingly, signaling via the IL-2/STAT5 axis is also required for the differentiation of the TH1 cell type. Our lab recently found that IL-2 signaling induces expression of the Ikaros Zinc Finger (IkZF) transcription factor Eos (Ikzf4) in TH1 cells, and that Eos positively regulates TH1-specific gene expression. Given the requirement for IL-2 signaling in TH2 development, we hypothesized that Eos may also play a role in TH2 differentiation. Indeed, we found that Eos expression was increased in TH2 cells at both the transcript and protein level as compared to TH0, TH1, and TFH-like cells. We also found that Eos knockdown resulted in a significant decrease in the expression of the canonical TH2 genes Il4 and Il13. When we cultured Eos-deficient cells in TH2-polarizing conditions, we similarly observed a decrease in Il4 and Il13 expression, as well as reduced expression of Il2ra and Il2rb. Eos-deficient TH2 cells also displayed decreased expression of Prdm1, the gene encoding Blimp-1, which represses the expression of alternative T helper cell gene programs in TH2 cells. Taken together, these data support a novel, positive role for Eos in the regulation of the TH2 gene program.
Tbet provides survival advantage to Tregs during Type 1 inflammation
Authors: Akkaya Billur , Akkaya Munir , Al Souz Jafar A , Holstein Amanda H , Maz Mitra , Kabat Juraj , Kamenyeva Olena , Shevach Ethan M 
Published: January 2023

Abstract
Regulatory T-cells (Tregs) comprise subgroups with transcriptional programs similar to helper T-cell lineages. To visualize Tbet expression by Tregs during a T helper 1 (Th1) driven inflammation induced by Complete Freund’s Adjuvant in vivo, we imaged Tregs in the lymph nodes of a Tbet.ZsGreen-Foxp3.RFP mouse. While the majority of conventional Foxp3+ Tregs, resided within the T-cell zone, Tbet+Foxp3+ Tregs localized to the interfollicular zone that also contained the recently activated Th1 cells. To understand whether Tbet serves merely as a marker of activation or plays an actual role in Treg function, we generated bone marrow chimeras from Tbet+/+ and Tbet−/− mice. The peripheral Treg pool in chimeric mice was equally constituted by the Tbet+/+ and Tbet−/− cells. However, when the mice were challenged with Plasmodium chabaudi, a parasite that initiates a strong systemic Th1 response, the Treg compartment was significantly dominated by Tbet+/+ Tregs that displayed increased Tbet expression over time. While Tbet+/+ and Tbet−/− Tregs displayed similar activation status and proliferation, Tbet−/− Treg were more prone to apoptosis. Furthermore, Tbet−/− Tregs expressed lower levels of the ATP ectonucleotidase CD39 that was more pronounced during the peak of infection. Pharmacological inhibition of the activity of CD39 increased apoptosis of Tbet+/+ but not Tbet−/− Tregs in an ATP enriched culture in-vitro, suggesting a positive correlation between the availability of Tbet, CD39 activity and viability. Taken together, Tbet may preserve the ability of Tregs to cope with elevated toxic extracellular ATP at the inflammation site by tuning their CD39 expression or activity.
Co-Stimulation–Induced AP-1 Activity is Required for Chromatin Opening During T Cell Activation
Authors: Barski Artem , Yukawa Masashi , Jagannathan Sajjeev , Kartashov Andrey V , Chen Xiaoting , Weirauch Mathew T 
Published: January 2023

Abstract
Activation of T cells is dependent on organized and timely opening and closing of chromatin. Herein, we identify AP-1 as the transcription factor that directs most of this remodeling. Chromatin accessibility profiling showed quick opening of closed chromatin in naïve T cells within 5 hours of activation. These newly open regions were strongly enriched for the AP-1 motif, and indeed, ChIP-seq demonstrated AP-1 binding at more than 70% of them. Broad inhibition of AP-1 activity prevented chromatin opening at AP-1 sites and reduced expression of nearby genes. Similarly, induction of anergy in the absence of co-stimulation during activation, was associated with reduced induction of AP-1 and a failure of proper chromatin remodeling. The translational relevance of these findings was highlighted by the substantial overlap of AP-1–dependent elements with risk loci for multiple immune diseases, most notably multiple sclerosis. Our findings define AP-1 as the key link between T cell activation and chromatin remodeling.
Bach2 attenuates T cell receptor-dependent transcription to fine-tune regulatory T cell differentiation
Authors: Sidwell Tom , Liao Yang , Vasanthakumar Ajithkumar , Shi Wei , Kallies Axel 
Published: January 2023

Abstract
The differentiation of regulatory T (Treg) cells is strictly controlled by T cell receptor (TCR) signals. However, the downstream regulators of this process are incompletely understood. Here we have found that Bach2 blocks the genomic binding of the TCR-induced transcription factor IRF4, attenuating TCR-dependent transcriptional programs to fine-tune Treg cell development and differentiation.
In the absence of Bach2 we observed an increase in TCR-driven Treg cell outcomes, including the enhanced differentiation of effector Treg cells and thymic Treg precursor cells, and a reduction in peripheral Treg cell differentiation. Additional loss of the TCR-responsive transcription factor IRF4 was sufficient to normalise frequencies of each of these Treg cell populations in the absence of Bach2. Transcriptomic analysis identified significant deregulation of gene expression in Bach2-deficient cells which was dependent upon IRF4 expression. Assessing genome-wide occupancy of these transcription factors, we found Bach2 to restrict access of IRF4 to most of its genomic binding sites. Together, these data indicate that Bach2 inhibits IRF4-dependent transcription by blocking its access to their shared binding sites.
Our work reveals Bach2 and IRF4 to drive opposing programs in Treg cell development and differentiation. Bach2 maintains the functional quiescence of Treg cells, in large part by blocking the genomic binding of IRF4 to attenuate the transcriptional program of TCR signalling.
DDX5 regulates chromatin lncRNAs to direct T cell programs
Authors: Ma Shengyun , Zhou Bing , Abbasi Nazia , Luo Claire , Yeo Gene W. , Fu Xiangdong , Huang Wendy Jia Men 
Published: January 2023

Abstract
Recent studies uncovered the growing role of long non-coding RNAs (lncRNAs) in T cell biology. However, little is known about the lncRNAs that localize on the T cell chromatin (T-chrRNAs) with critical roles in gene expressions at the transcription and post-transcriptional level. Using the GRID-seq approach, we uncovered the top 18 T-chrRNAs and their chromatin occupancy in primary mouse CD4+ T helper cells in both the naïve and differentiated states. The chromatin binding of these T-chrRNAs revealed surprising stage-specific clustering patterns and mobilization during development and T cell differentiation. Our eCLIP assay showed that many of these T-chrRNAs interact directly with the DDX5, a nuclear residing RNA binding protein with ATPase activity.
Th17 are unique CD4+ T-cell subset characterized by production of IL-17 and play an important role in inflammation and autoimmunity. At low TGFβ concentration, DDX5 is required for proper Th17 cytokine expression. Our ATAC-seq results suggest that DDX5 knockout Th17 cells fail to maintain chromatin accessibility at numerous regulatory regions, including the super-enhancer at the Il17a-Il17f locus. Moreover, GRID-seq data on WT and DDX5 knockout Th17 cells identified a subset of T-chrRNAs dependent on DDX5 for their proper chromatin localization. In particular, Malat1 is recruited to key Th17 loci in a DDX5 dependent manner. Similar to the DDX5-knockout Th17 cells, CRISPR-Cas targeting of the DDX5 bound regions of Malat1 results in loss of Th17 effector function. Better understanding of the localizations, functions, and upstream regulatory mechanisms governing T-chrRNAs physiology will provide new opportunities for therapeutic intervention to treating T cell mediated diseases.
Electrophilic nitro-fatty acids suppress psoriasiform dermatitis through the inhibition of STAT3 and NF-κB
Authors: Wang Peng , Killeen Meaghan , Mathers Alicia R 
Published: January 2023

Abstract
Psoriasis is a systemic, immune-mediated disorder, characterized by chronic inflammatory skin and joint manifestations. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of endogenous electrophilic nitro-fatty acids that exert potent anti-inflammatory effects. To study the therapeutic potential of nitro-fatty acids on psoriasis, we employed various experimental models of psoriasis including direct induction and genetically engineered murine models. Our studies demonstrated that oral treatments of nitro-oleic acid (OA-NO2) prior to imiquimod (IMQ) or IL-23 applications, significantly inhibited the induction of psoriasis-like skin inflammation. Consistently, oral OA-NO2 downregulated the production of inflammatory cytokines (IL-1β, IL-6 and IL-17a) in the skin. Moreover, utilizing the chronic K14-VEGF and K5-IL-17C murine models, we determined that oral OA-NO2 had both a preventative and therapeutic effect on psoriasiform inflammation. Further in vitro experiments demonstrated that OA-NO2 impaired STAT3 phosphorylation and translocation to the nucleus, which resulted in decreased keratinocyte proliferation. Importantly, OA-NO2 decreased the basal expression and IL-17A-induced expression of IL-6 in normal human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Overall, our results confirm the critical role of both STAT3 and NF-κB, in psoriasiform dermatitis, and highlight the potential of nitrofatty acids as therapeutic agents for the treatment of this cutaneous inflammatory disease.
Chromatin interaction maps of active cis-regulatory elements in primary human immune cells reveal extensive overlap with disease-associated genetic variants
Authors: Chandra Vivek , Bhattacharyya Sourya , Schmiedel Benjamin J. , Madrigal Ariel , Ay Ferhat , Vijayanand Pandurangan 
Published: January 2023

Abstract
Surveys of purified human immune cell types have revealed that common genetic variants have profound effects of gene expression in a highly cell-specific manner. However, it has been challenging to determine the mechanisms behind cell-specific regulatory effects as well as to pinpoint the potentially functional variants in dense haplotype blocks. Here, we performed genome-wide ChIP-Seq and proximity ligation-assisted ChIP-seq assays (HiChIP) for the H3K27ac modification to capture physical interactions between active cis-regulatory elements and their target gene promoters for 5 common and diverse immune cell types from 6 donors. The generated interaction maps identified long-range loops (over 20kb) for more than 90% of active cis-regulatory regions. We found that majority of the cis-regulatory interactions were highly cell-specific, which in turn correlated with cell-specific transcription factor binding motifs and gene expression patterns. Nearly 10% of expression quantitative trait loci (eQTLs), including disease-associated eQTLs and GWAS SNPs, were located at active cis-regulatory regions that interacted with the target genes of eQTLs (eGenes), thus allowing us to narrow down potentially functional/causative QTLs. Majority of cis-eQTLs that are specific to only a single cell type overlapped cis-regulatory elements that showed interactions with the promoter of their target eGenes only in that specific cell type. Our study thus provides a comprehensive interaction map of active regulatory elements for each of the 5 immune cell types across multiple donors and highlights the cell type-specificity of potentially functional variants and interactions linking them to genes in human disease.
Lipid droplets in mouse thymus express immune molecules and inhibit antigen-specific CD4+ T cell responses
Authors: Bamezai Anil K , Robinson Sarah , Humrich Sarah 
Published: January 2023

Abstract
Lipid droplets (LDs) are vesicles present inside a wide variety of cells. LDs play a vital role in storing neutral lipids as a source for nutrients. While LDs are readily detected intracellularly, their extracellular presence is not widely reported. The cellular origins of LDs and the functions they serve in the thymus remain largely unknown. We detected presence of LDs in the mouse thymus and lymph nodes. We have investigated the proteins expressed by mouse thymic LDs and their functional role. To facilitate this inquiry, we first developed a novel method to isolate and quantify LDs from the thymus. Isolated LDs were analyzed by flow cytometer after staining with either fluorescent-tagged antibodies against immune cell proteins, or a lipid staining orange dye oil stain scarlet 6G. We report that the thymic LDs are heterogeneous in size (range 5 to 100 μm). LDs, on their membrane, express many immune molecules, including T cell receptor αβ in significant amounts. Thymic LDs do not express MHC proteins and are functionally incompetent to serve as antigen presenters. However, when included in antigen presenting assays using bona fide antigen presenting cells, LDs inhibit CD4+ T cell responses. We conclude that LDs found in the thymus express immune molecules on their membrane. While LDs do not directly present antigens to CD4+ T cells, however, their inclusion in cell cultures inhibit antigen-specific clonal expansion of CD4+ T cells in the presence of APC and an appropriate antigen.
15(S)-HETE plays a regulatory role in the immune inflammatory responses
Authors: Choe Jongseon , Kwon Bongjae 
Published: January 2023

Abstract
Arachidonic acids are subjected to the enzymatic transformation by PGH2 synthase or lipoxygenase upon the liberation from the membrane phospholipid. Using in vitro and in vivo experimental models, we have investigated the cellular and molecular mechanisms in the production and function of arachidonic acid metabolites. Here we report that a downstream product of 15-lipoxygenase, 15-S-hydroxyeicosatetraenoic acid (15-S-HETE) is not produced by human follicular dendritic cell (FDC)-like cells but exerts a regulatory effect on prostaglandin production by this type of cells. 15-S-HETE appears to derive from endothelial cells. FDC-like cells, which were isolated from human tonsil, do not express 15-lipoxyenase or 5-lipoxygenase but metabolize 15-S-HETE into downstream products. Immunoblotting analysis and results with chemical inhibitors imply that 15-S-HETE acts on FDC-like cells via PPAR-γ and leukotriene B4 receptor 2. 15-S-HETE enhances or inhibits the expression of PGH2 synthase and resultant prostaglandin production in FDC-like cells, which depends on the types of co-stimulation. Based on these data, we suggest a novel cellular and molecular pathway of immune regulation mediated by arachidonic acid metabolites.
Basophil-derived tumor necrosis factor can enhance immune responses in a sepsis model in mice
Authors: Piliponsky Adrian Martin , Shubin Nicholas J , Lahiri Asha , Truong Phuong , Clauson Morgan , Niino Kerri , Tsuha Avery , Nedospasov Sergei A , Karasuyama Hajime , Reber Laurent , Tsai Mindy M , Mukai Kaori , Galli Stephen J 
Published: January 2023

Abstract
Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short lifespan, suggesting that basophils have beneficial roles in maintaining health. However, these roles are not fully defined. Here, we demonstrate that basophil-deficient mice exhibited reduced bacterial clearance, and increased morbidity and mortality, in the cecal ligation and puncture (CLP) model of sepsis. Among the several pro-inflammatory mediators we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. TNF is critical for mounting effective immune responses against certain pathogens. Accordingly, we investigated whether basophil-derived TNF can significantly contribute to the innate immune response triggered by CLP. For this purpose, we generated a conditional mouse in which TNF production was specifically ablated in basophils. Serum and intraperitoneal TNF levels were significantly reduced in mice with genetic ablation of Tnf in basophils after LPS administration, indicating that basophils contribute to increased TNF levels during LPS-induced endotoxemia. Furthermore, mice with basophils deficient in TNF exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality after CLP. Taken together, our studies in mice show that basophils can enhance the innate immune response against bacterial infection and help to prevent sepsis.
NLRC4 deficiency enhances macrophage and T cell responses in polymicrobial sepsis
Authors: Paudel Sagar , Ghimire Laxman , Jin Liliang , Jeyaseelan Samithamby 
Published: January 2023

Abstract

Rationale
Sepsis, a dysregulated systemic host inflammatory response to infection with organ failure, is leading cause of death in non-coronary intensive care unit worldwide. Recently, the NLRC4 inflammasome has been implicated in sensing pathogens and regulating inflammation during microbial infections. However, the role of NLRC4 in sepsis-induced immunosuppression, specifically macrophage dysfunction and T cell loss, is poorly understood.

Methods
We performed cecal ligation and puncture (CLP) to induce polymicrobial sepsis in wild type (C57BL6) and NLRC4-gene deficient (KO) mice. Cellular influx, bacterial burden, and host survival were measured. Macrophages were depleted using Clodronate liposomes. Depletion of lymphocytes, frequency of IFN-γ producing T cells, expression of costimulatory molecules in peritoneal macrophages were examined using flow cytometry.

Results
NLRC4 KO mice were protected from CLP-induced lethality. Furthermore, NLRC4 KO mice had reduced cellular influx, cytokine storm (IL-1b, TNF-a, MCP-1, CXCL-1, CXCL2), and bacterial burdens following CLP. NLRC4 KO mice were protected from sepsis-induced impairment of macrophage function and loss of CD4 and CD8 T cells. Peritoneal macrophages (CD11b+F4/80+) were protected from sepsis-induced loss of MHCII and CD86. Intriguingly, macrophage depletion prior to polymicrobial sepsis eliminated the NLRC4-mediated survival advantage. NLRC4 KO mice had increased frequency of IFN-γ producing T cells post-CLP.

Conclusions
These findings identify NLRC4 as a negative regulator of macrophage and T cell responses in sepsis and its selective inhibition as a potential therapeutic strategy to augment host immunity in sepsis.