bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNF deficiency induces breach of B cell tolerance by altering the homeostasis of the regulatory signals in activated B cells of lupus prone mice
Authors: Quach Tam D , Diadhiou Catherine M. M. , Raparia Chirag , Martinez Shani , Tao Haiou , Tükel Çağla , Jacob Chaim O. , Davidson Anne 
Published: January 2023

Abstract
The induction of autoantibodies and autoimmunity in patients treated with TNF inhibitors (TNFi) is well-known, but the mechanism by which TNFi induce breach of B cell tolerance is not known. TNF deficiency induces TFH and TH17 cell expansions and disrupts germinal centers (GC), that regulate high affinity antigen specific antibody production and autoreactive B cell selection. We found that TNF deficiency in Sle1 mice (Sle1.TNF−/−) induced high titers of germline encoded, T-dependent IgG anti-cardiolipin. Upon treated with TLR9 ligand (DNA/curli amyloid protein), Sle1.TNF−/− mice developed high IgG anti-dsDNA; although CD95+PNA+/GL7lowGC phenotype B cells were induced, they did not form GC nor acquire dark zone phenotype, and their Ig heavy chains accumulated low numbers of mutations. Similarly, without proper GC, GC phenotype B cells were found in the TNFR1/2−/−NZM2328 mice, who developed accelerated lupus, suggesting disturbed GC by TNF deficiency dysregulated GC phenotype B cell selection. Using an antibody to Neu5Gc (N-Glycolylneuraminic acid, a CD22 high affinity ligand which is the hydrolyzed product of GL7 ligand, N-acetylneuraminic acid, Neu5Ac), we found that GC phenotype B cells from TNF deficient mice failed to stop hydrolyzing Neu5Ac to Neu5Gc, suggesting a failure in recruitment of CD22 to the BCR complex upon activation. Furthermore, activated B cells from Sle1.TNF−/− mice constitutively expressed high level of pS6 and SHIP-1; whereas, additional stimulants, anti-Ig and/or anti-CD40, were required to induce pS6 expression in those of the Sle1 mice. Here, we report a possible mechanism by which TNF deficiency alters the homeostasis of regulatory molecules such as CD22 and FcgRIIB, and thus activated B cell selection.
AMPKα1 in B cells promotes memory B cell longevity and mitochondrial homeostasis while dampening antibody synthesis
Authors: McLetchie Shawna , Cho Sung Hoon , Basso Paulo , Boothby Mark Robin 
Published: January 2023

Abstract
Emerging evidence indicates that metabolic programs regulate B cell activation and antibody responses. However, the metabolic mediators that support the durability of the memory B cell and long-lived plasma cell populations are not fully elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved serine/threonine kinase that integrates cellular energy status and nutrient availability to intracellular signaling and metabolic pathways. Here, we use genetic mouse models to show that B cell restricted loss of the catalytic subunit, AMPKα1, leads to a defect in the long-term survival of the memory B cell population. AMPKα1-deficient memory B lymphocytes exhibited aberrant mitochondrial activity including impaired mitophagy and decreased mitochondrial spare respiratory capacity. In contrast, AMPKα1 was dispensable for the stability of the bone marrow-resident long-lived plasma cell population yet its absence led to increased rates of Ig synthesis and elevated serum antibody concentrations elicited by immunization. Collectively, our findings fit a model in which AMPKα1 supports longevity in the memory B cell compartment by promoting mitochondrial homeostasis but restrains rates of immunoglobulin production by plasma cells.
Lipin-1 transcriptional co-regulatory activity enhances anti-inflammatory responses in lipid-loaded macrophages and induces atheroprotection
Authors: Blackburn Cassidy , Schilke Robert M , Vozenilek Aimee E , Finck Brian N. , Woolard Matthew D 
Published: January 2023

Abstract
Metabolic disorders, like atherosclerosis, increase the lipid burden in macrophages leading to chronic inflammation. How macrophages sense and respond to excess lipid is not well understood. Lipin-1 is a phosphatidic acid phosphatase that also functions as a transcriptional co-regulator and is critical to regulating lipid burden in cells. We have shown that lipin-1 enzymatic activity promotes macrophage pro-inflammatory responses and accelerates atherosclerosis. Lipin-1 transcriptional co-regulatory activity binds to and augments transcription factors such as PPARγ. PPARγ increases macrophage anti-inflammatory responses. The objective of this study was to determine if after increased lipid burden in macrophages, lipin-1 transcriptional co-regulatory activity tailors PPARγ to promote anti-inflammatory responses by macrophages and reduce atherosclerosis. Upon RNA analysis in lipid stimulated macrophages, we demonstrated lipin-1 tailors PPAR-associated gene expression and promotes anti-inflammatory responses. Using mice that lack just lipin-1 enzymatic activity or all lipin-1 in myeloid cells, we examined the contribution of lipin-1 transcriptional co-regulatory activity to atherosclerosis progression. Our mice lacking both myeloid-associated lipin-1 activities had larger, more necrotic plaques. Using Nanostring analysis, we observed increased expression of pro-inflammatory genes such as IL-23 in the plaque and increased IL-23 in serum suggesting lipin-1 transcriptional co-regulatory activity in macrophages promotes anti-inflammatory responses to reduce atherosclerosis. Our work highlights the dynamic nature of lipid metabolism on macrophage function and contribution to disease progression.
Cationic Cyclodextrins Regulate Nucleic Acid-induced Proinflammatory Responses
Authors: Sharma Rahul , Venkatadri Rajkumar , Dogan Murat , Palakurthi Sushesh , Mohammad Saleh , Hudspeth Andrew , Palakurthi Srinath 
Published: January 2023

Abstract
Cyclodextrins (CDs) were discovered over a century ago for their ability to complex with several macromolecules and have found use in pharmaceutical industry to enhance solubility of drugs. Cationic CDs can bind nucleic acids (NA) and are being tested for delivery of NA to cells. Extracellular NAs can act as pro-inflammatory triggers and their inefficient clearance may activate Toll-like receptors (TLR) and contribute to autoimmune diseases such as lupus. We hypothesized that NA-binding CD (NABCD) may be used for scavenging extra-cellular NA to prevent pro-inflammatory responses. Here we investigated whether NABCD can modulate immune activation triggered by DNA or NA-TLR ligands. Indeed, in vitro assays using bone marrow derived macrophages (BMM) showed that NABCD induced a statistically significant inhibition of the expression of innate immune activation genes including Mx1, Prkr, Il1b and Tnfa when exposed to DNA or poly I:C. Treatment of C57BL/6 mice with TLR ligand polyI:C induced an acute pro-inflammatory response indicated by upregulation of interferon response genes and cytokine production. Treatment with NABCD not-only attenuated the innate-immune activation, but also modulated the adaptive immune response by significantly preventing a Th1 skewing of the immune response. The NABCD-treated mice also had higher numbers of IL-10 producing CD4 T-cells and more Foxp3+T-regulatory cells in the spleens as compared to mice treated only with polyI:C. Our data indicate a feasibility for the use of NABCD for modulating NA-induced proinflammatory responses and may find applications for treatment of autoimmune diseases such as lupus, where extra-cellular DNA plays a pathogenic role.
Mononuclear phagocytes drive Mertk-dependent T cell regulation at autoimmune and tumor sites
Authors: Whitesell Jennifer C , Lindsay Robin S , Dew Kristen , Rodriguez Erika , Tracy Dayna , Sandor Adam M. , Yannacone Seth , Jacobelli Jordan , Friedman Rachel S. 
Published: January 2023

Abstract
Understanding mechanisms of immune regulation is key to developing effective immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes (MNPs) in regulating effector T cells in type 1 diabetes and melanoma. MNPs in the islets impaired T cell responsiveness to antigen by preventing antigen-mediated T cell arrest. MNPs in the autoimmune lesion express the TAM family receptor tyrosine kinase Mertk which functions in efferocytosis. Inhibition or deficiency of Mertk led to a release from T cell regulation characterized by enhanced T cell arrest in pre-diabetic islets and at the tumor site. T cell arrest was accompanied by increased T cell-antigen presenting cell interactions as well as increased antigen experience and effector function by T cells in the islets. Single cell RNA-seq analysis of islet MNPs identified multiple myeloid subsets. Inhibition of Mertk induced the most significant changes in gene expression among the islet resident macrophages including upregulation of inflammatory cytokine and adhesion genes. In the NOD mouse model, inhibition of Mertk-dependent T cell regulation culminated in the rapid acceleration of autoimmune pathology and disease. In human islets, the number of Mertk-expressing cells were increased in remaining insulin-containing islets from type 1 diabetic patients, suggesting that they might have a protective role in human disease. These data indicate that Mertk signaling in MNPs drives T cell regulation that functions specifically at the disease site in peripheral tissues through a mechanism that prevents T cell arrest and response to antigen.
E3 Ubiquitin Ligase Cbl-b Restrains Priming of Pathogenic Th17 Cells via Inhibiting IL-6 Production by Macrophages
Authors: Tang Na , Zeng Qiuming , Guo Hui , Zhang Jian 
Published: January 2023

Abstract
E3 ubiquitin ligase Cbl-b is involved in the maintenance of a balance between immunity and tolerance. Mice lacking Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis (EAE), a Th17-mediated autoimmune disease. However, how Cbl-b regulates Th17 cell response remains unclear. In this study, utilizing adoptive transfer and cell type-specific Cblb knockout strains we show that Cbl-b expression in macrophages but not T cells or dendritic cells (DCs) restrains the generation of pathogenic Th17 cells and the development of EAE. Cbl-b inhibits the production of IL-6 by macrophages induced by the signaling derived from C-type lectin receptors, which directs T cells to generate pathogenic Th17 cells. Therefore, our data are the first to unveil a previously-unappreciated function for Cbl-b in the regulation of pathogenic Th17 response.
Investigating the role of mast cell activation by nitrogen mustard in lung toxicity
Authors: Cruz-Hernandez Angela Alexandra , Mendoza Ryan , Brown Jared M 
Published: January 2023

Abstract
Chemical warfare agents (CWA) were widely used during the Gulf War (1990–1991) and as a result left ~30% of veterans suffering from Gulf War Illness (GWI). The vesicating agent, sulfur mustard (SM) is one of the most noteworthy CWA used during this time. Prior research has demonstrated that SM targets the bone marrow and has the potential to influence immune cells. In the skin, SM is reported to induce mast cell degranulation. Therefore, the aim of this study was to determine if nitrogen mustard (NM) (a surrogate for SM) promotes activation of mast cells. Using murine bone marrow derived mast cells (BMMCs) we assessed activation through degranulation, eicosanoid expression, and pro-inflammatory cytokine production. While NM exposure (1μM–50μM) did not result in mast cell degranulation, we observed a 30-fold increase of cyclooxygenase-2 (COX-2) mRNA production at 10μM at 6h. In addition, IL-6 production by BMMCs post 24h exposure to NM demonstrated a dose dependent increase indicative of late phase activation. To further demonstrate a pivotal role for mast cells in NM exposure, we compared the effects of NM exposure on lung pathology between C57BL/6 and B6.Cg-KitW-sh/ HNihrJaeBsmJ (mast cell deficient) mice. Significant lung injury was observed in C57BL/6J following NM exposure at 72 hrs as indicated by H&E staining. In contrast, significantly less injury was observed in mast cell deficient mice. Similarly, increases in total protein and IL-6 was observed in C57BL/6 mice but not mast cell deficient mice. These results suggest that mast cells play a prominent role in the injury induced by NM and may contribute to symptoms observed in GWI.
Genetic regulation of nitric oxide-dependent mitochondrial metabolism and immune function in dendritic cells
Authors: Snyder Julia Priscilla , Lahue Karolyn , Krementsov Dimitry N , Amiel Eyal 
Published: January 2023

Abstract
Dendritic cell (DC) activation is characterized by a rapid “metabolic switch” towards increased glycolysis that supports maturation. Sustained glycolysis post-activation is a requirement for survival in DC subsets that express inducible nitric oxide synthase (iNOS), due to the production of nitric oxide (NO) which acts as an inhibitor of mitochondrial respiration. Long-term metabolic reprogramming in activated DCs has almost exclusively been studied in the strain C57BL/6, which experience loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we generated and compared cells from C57BL/6 mice to the wild-derived genetically diverse PWD/PhJ (PWD) strain. We show attenuated iNOS induction and significantly lower NO production in PWD DCs. Decreased NO production allows PWD DCs to maintain mitochondrial respiration following activation, and significantly alters their glucose-dependent carbon flux through the TCA cycle compared to C57BL/6 DCs. We utilize a consomic strain which includes the PWD chromosome segment containing the iNOS locus on an otherwise C57BL/6 genetic background to demonstrate that intrinsic differences in the iNOS locus drive differential iNOS regulation. We demonstrate that differential iNOS regulation amongst these strains impacts DC post-activation survival and immune effector functions. These studies provide a more comprehensive understanding of NO-driven metabolic reprogramming in the murine myeloid lineage and establish a natural genetic model for investigating the contribution of NO in regulating the interplay between DC metabolism and immune function.
Maternal hypothyroxinemia alters the immune function of the adipose tissue in the adult the progeny
Authors: Gutierrez Barbara Cecilia , Alba Arturo , De luca Natalia , Vecchiola Andrea , Osses Maricarmen , Gomez Felipe , Santos Johana , Mendez Luis , Aguayo Daniel , Opazo Maria Cecilia 
Published: January 2023

Abstract
Obesity and thyroid hormone deficiency are global problems. Chile has 31,2% of obesity. Obesity is characterized by adipose tissue, that’s able to influence the immune system. Gestational environment can increase the offspring susceptibility to have obesity. It’s been suggested that maternal hypothyroxinemia (HTX) could be a factor for obesity development in the offspring imprinting the adipose tissue contributing to the altered immune response seen in HTX progeny.
The aim of this work is to evaluate the effect of HTX in adipose tissue in the progeny and its influence on the adipocyte immune function.
For this purpose, weight and body fat content of the offspring gestated or not under HTX using In vivo MRI was asess. Area and number of adipocytes from offspring conditions was evaluated using a deep convolutional neural network approach. Cell infiltration was also analyzed. Expression of cytokines as PPARs and leptin were evaluated. Adipose tissue infiltrating cells were analyzed by FACS. In vitro, the differentiation capacity of control and HTX pre-adipocytes using Oil red staining and quantification and measure adipokine an cytokine production by these cells was evaluated.
We show that the HTX offspring present an increased body fat content. Image analysis showed an increase in the number and area of the HTX adipocytes. An increased capacity of HTX pre-adipocytes to differentiate to adipocytes was seen. Alteration in the expression of cytokines, PPARs and leptin and an increase in cell infiltration with more predominant activated CD4+ T cells and monocytes was observed.
This work proves that maternal HTX induces alterations of the adipose tissue of the progeny that could contribute to the susceptibility of the HTX to autoimmune diseases.
Transcriptional profiling predicts behavioral performance in experimental mouse model of traumatic brain injury (TBI)
Authors: Jiao Yun , Faden Alan , Sabirzhanov Boris , Stoica Bogdan , Szeto Gregory L. , Leach Jennie 
Published: January 2023

Abstract
Traumatic brain injury (TBI) is a prevailing cause of disability and death. There are no curative therapies or robust predictors of long-term neurodegenerative disease. Treatment is challenging due to poor understanding of the cellular responses and mechanisms underlying TBI. We linked transcriptional profiling, cytokine profiling, and behavioral scoring in experimental TBI to discover new insights into immune-mediated mechanisms of TBI. Mice received ipsilateral moderate controlled cortical impaction. Luminex analyses showed upregulation of inflammatory cytokines in injured cortex, hippocampus, and spinal cord. Neurobehavioral evaluations were performed, then hippocampi isolated at 28d post-TBI for RNAseq. Pathway analyses of upregulated genes were functionally enriched for glial activation, proliferation, and neuronal development. Genes involved in synaptic transmission, glutamate receptor signaling, and neuronal migration were downregulated. Partial least squares (PLS) regression successfully modeled the relationship between differentially expressed genes and behavioral scores (R2=0.94). A core 10-gene signature predicted TBI severity and behavioral score. PLS discriminant analysis (PLSDA) classified TBI severity. VIP scores were used to define a 20-gene signature in TBI based on high VIP score, high fold change, and contribution to biological function. A PLSDA model using only these 20 genes was cross-validated by bootstrap method (AUROC=0.93), indicating that these genes may identify the critical TBI-altered processes. Altogether, our analyses revealed TBI-related biological pathways, potential therapeutic targets, and gene signatures as biomarkers for TBI severity and behavioral outcomes.
A functional interaction between plasmacytoid dendritic cells (pDCs) and CD169+ macrophages in the bone marrow regulates pDCs production of type I interferon during severe malaria
Authors: Moore Jamie M , Fooksman David R , Lauvau Gregoire 
Published: January 2023

Abstract
While type I interferon (IFN-I) is central to antiviral immunity, it can also promote pathology in bacterial and parasitic infections, and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) are able to produce 1,000× more IFN-I than any other cell upon sensing of nucleic acid ligands by TLR7 and TLR9. pDCs can obtain their ligands via direct cell-cell interactions, yet what regulates these interactions and whether pDCs need to receive additional signals to secrete IFN-I is unknown. Using a mouse model of severe malaria, we showed that pDCs initiate IFN-I production in the bone marrow (BM) of infected mice, and that this required CD169+ macrophages (MPs). IFN-I production by pDCs was also dependent on TLR7 and STING sensing in pDCs and CD169+ MPs, respectively. Through intravital microscopy (IVM), we further revealed that pDCs arrest and form clusters with CD169+MPs in the BM of malaria infected mice when peak IFN-I production occurs. Here, we hypothesize that pDC-MP interactions are required to license pDCs to produce IFN-I. We found that pDCs fail to arrest and form clusters with MPs in Tlr7−/− mice, and that blocking chemotaxis prevents pDC-MP interactions and subsequent IFN-I production, consistent with our hypothesis. Interestingly, while pDCs do not make IFN-I in STING-deficient mice, they still arrest and cluster around MPs. These clusters are much larger than in WT mice, suggesting that pDCs fail to receive another STING-dependent signal. Collectively, these results support a model in which pDC production of IFN-I is tightly regulated through a functional interaction with CD169+ MPs providing activating ligands and stimulatory signals. Targeting this interaction may represent a novel way to tune levels of IFN-I produced by pDCs.
Inhaled tigecycline induces change in immune cell modulation that synergizes with antimicrobial activity in chronic pulmonary Mycobacterium abscessus disease
Authors: Pearce Camron M , Walz Amanda , Gonzalez-Juarrero Mercedes , Ali Zohaib , Munoz-Gutierrez Juan , van Ingen Jakko 
Published: January 2023

Abstract
Pulmonary Mycobacterium abscesssus (pAMB) infection is particularly challenging to treat because this bacillus displays intrinsic antibiotic resistance to most front-line drugs. Tigecycline, a glycyclcycline tetracycline, shows potent bactericidal effects against pMAB, while successfully evading bacterial resistance mechanisms. Tigecycline is FDA approved as a twice daily IV administration but provokes intolerable side effects in patients. More than its potent antimicrobial effects, tigecycline has demonstrated immunomodulatory properties observed in preclinical animal models of bacterial infection. We hypothesized that inhaled therapy of tigecycline reduces side effects and improve efficacy against pMAB. GM-CSF knockout mice with pMAB were treated daily for 28 days with aerosols of tigecycline at 0.25, 1.25 and 2.50 mg/dose. Thereafter, bacterial burden was assessed, and samples were prepared for immunophenotyping of lymphocyte and myeloid cell populations through H&E staining and IHC techniques. The results demonstrated that treatment with aerosols of tigecycline to mice with pAMB was tolerated and highly effective at reducing bacterial burden. Furthermore, this therapy was associated with the influx of macrophages and lymphocytes in both perivascular zones and granulomatous-like formations. There was also an increase in alveoli lined by hypertrophied cells with vesicular nuclei, suggesting induced Type II cell hyperplasia. To summarize, inhaled tigecycline not only demonstrated bactericidal effects against pMAB, but it invokes unique immunomodulatory effects that appear to aid the significant reduction in pulmonary bacteria.
Antigen presentation by CNS-resident microglia and macrophages is required for antiviral CD8 T cell responses in the brain following CNS viral challenge
Authors: Goddery Emma , Lipovsky Chloe , Jin Fang , Hansen Michael , Pavelko Kevin D , Johnson Aaron J 
Published: January 2023

Abstract
CD8 T cell responses are essential for clearance of infections and tumors in the central nervous system (CNS). Under homeostatic conditions, T cell access to the CNS parenchyma is restricted. An intricate process of T cell reactivation by antigen presenting cells (APCs) at CNS barriers is thought to allow activated antigen-specific T cells to infiltrate the parenchyma during neurological disease. The role of CNS-resident APCs during CD8 T cell infiltration of the CNS parenchyma is unclear. We hypothesized that microglia and brain-associated macrophages (BAMs) are APCs critical for antigen specific CD8 T cell reactivation and CNS infiltration. To test this hypothesis, we generated mice with tamoxifen-inducible deletion of MHC class I on microglia and BAMs by crossing CX3CR1creER mice with H-2Db fl/fl mice (Db cKO). We challenged these mice with intracranial infection of Theiler’s murine encephalomyelitis virus (TMEV), which generates a robust CD8 T cell response against a Db restricted antigen (VP2121–130) in the brain. At 7 days post infection (dpi), brain infiltrating Db:VP2-specific CD8 T cells were reduced in Db cKO mice compared to control, while peripheral priming of CD8 T cells was unaffected. Unexpectedly, inflammatory monocytes infiltrating the brain at 7 dpi were also reduced in Db cKO mice, indicating a role for microglia/BAMs and CD8 T cells in recruitment of inflammatory monocytes. Db cKO mice were able to clear virus, indicating functional antiviral responses against TMEV occur despite reduced immune infiltration. These results demonstrate that local antigen presentation by microglia and BAMs facilitates inflammatory monocyte recruitment and antigen-specific CD8 T cell responses in the brain after TMEV infection.