bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophils control autoreactive Th17 responses in spondyloarthritis
Authors: Asare-Konadu Kofi N , Vance Emily E , Sen Rouhin , Caplan Liron , Rosenzweig Holly L , Napier Ruth J 
Published: January 2023

Abstract
Spondylarthritis (SpA) refers to a group of autoimmune diseases characterized by inflammation of the spine (spondylitis) and joints (arthritis) including ankylosing spondylitis and psoriatic arthritis. Genetic studies suggest that autoreactive Th17 cells drive SpA pathogenesis and in support IL-17 blockade in the clinic moderates symptoms. Although Th17 responses appear to be key in driving symptomatic disease, less is understood of the underlying innate cellular mechanisms that contribute to the initiation of pathogenic T cells. Upon analysis of SpA patient cell blood count data (1,497 events) we discovered a positive correlation between the absolute number of neutrophils and disease severity. Thus, we sought to determine how dysregulated neutrophil responses might control autoreactive Th17 responses using an experimental model of SpA (SKG mice). SKG mice have a point mutation in Zap70 resulting in autoreactive Th17 cells that cause arthritis and spondylitis. When SKG splenocyte cultures were treated with monoclonal antibodies to CD3 and simultaneously co-incubated with autologous neutrophils for 72h we detected increased T cell activation status (CD69 expression) and production of IL-17 but not IFNγ compared to media only (no neutrophils) controls. Neutrophil-deplete SKG mice had reduced autoreactive Th17 responses and delayed onset of arthritis compared to neutrophil-replete controls, supporting a role for neutrophils in promoting autoreactive Th17 responses and the induction of disease. In conclusion our data reveal a role for neutrophils in pathogenesis of SpA, indicating that neutrophil modulating drugs could be considered as a future treatment strategy for SpA.
Supported by grants from VA (CDA-2 IK2BX004523 and Merit I01BX002180) and NIH (R01 EY025250)
GFI1 KO can develop allergic reaction independently from IL5 and ILC2 cells
Authors: Fraszczak Jennifer , Dalloul Zeinab , Moroy Tarik 
Published: January 2023

Abstract
The number of people living with a chronic inflammatory lung disease, such as asthma, is constantly increasing. The development of resistance to existing therapies and the fact that exposure to air pollution and particular matter are continuously increasing have made asthma a major health problem worldwide. We have observed that in mice lacking the transcriptional factor GFI1 (short for “Growth factor independent 1”) where ILC2 are not functional and IL5 is almost absent, a severe asthmatic inflammatory reaction can still be provoked with increased numbers of eosinophils in the airways. This finding strongly suggests that pathways other than those initiated by IL5/IL5R and ILC2 cells exist that play a major role in severe allergic asthma. We hypothesize that the situation in GFI1 KO mice reflects what it is observed in asthmatic patients that are resistant to the recent therapies. We further posit that GFI1 KO mice is a tool to discover new pathways involved in asthmatic reactions different from the known and established mechanisms involving IL5. We are using this unique mouse model (Gfi1 deficient mice) and high throughput genomic sequencing technologies with a specific bioinformatics approach to identify new molecules pathways mediating the inflammatory reaction in asthma. We expect to reveal new molecular signaling pathways that cause lung inflammation during an allergic asthma reaction, specifically those regulating eosinophil recruitment and activities. Our first results show that GFI1 KO seem to be able to support an allergic reaction though IL17 pathway and Th17 cells. We anticipate to identify of molecular targets, which could be used to develop new, more effective therapies for patients with severe allergic asthma.
β-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells
Authors: Lajiness Jacquelyn D , Amarsaikhan Nansalmaa , Tat Kiet , Tsoggerel Angar , Cook-Mills Joan 
Published: January 2023

Abstract
In humans and mice, offspring of allergic mothers are predisposed to development of allergy. In mice, allergic mothers have elevated β-glucosylceramides (βGlcCers) that are transported to the fetus via the placenta and to offspring via milk. Elevated βGlcCers increase numbers of fetal liver CD11c+CD11b+ dendritic cells (DCs) and offspring allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol and γ-tocopherol. It is not known whether βGlcCers and tocopherols directly regulate development of DCs. In this study, we demonstrated that βGlcCers (C16:0, C18:0, C18:1, and C24:1) increased development of GM-CSF-stimulated bone marrow-derived DCs (BMDCs) in vitro. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCer increased PKCα and PKCδ activation in BMDCs that was blocked by α-tocopherol. In contrast, γ-tocopherol increased BMDC PKCα and PKCδ activation and enhanced the βGlcCer-induced increase in PKCδ activation in a DC subset. Antigen processing per DC was minimally enhanced in βGlcCer-treated BMDCs and not altered ex vivo in lung DCs from pups of allergic mothers. However, lung DCs from pups of allergic mothers had an increased proportion of CD11b+CD11c+ DCs and exhibited enhanced stimulation of T cells ex vivo. Thus, βGlcCer, which is both necessary and sufficient for development of allergic predisposition in offspring of allergic mothers, directly increased development and PKC activation in BMDCs. Furthermore, this was modifiable by dietary tocopherols. This may inform design of future studies for approaches in the prevention or intervention in asthma and allergic disease.
Supported by grants from the NIH (U01 AI131337 (Cook-Mills), R01AI127695 (Cook-Mills)) as well as the Pediatric Scientist Development Program (Lajiness) and Marshall Klaus Perinatal Research Award (Lajiness)
Myeloid cell-specific IL4Rα deletion protects against mixed allergen-induced lung injury in mice
Authors: Choudhary Ishita , Vo Thao , Singamsetty Dhruthi , Paudel Kshitiz , Mao Yun , Lamichhane Richa , Patial Sonika , Saini Yogesh 
Published: January 2023

Abstract

Introduction
IL-4 and IL-13 play an essential role in the pathogenicity of allergic asthma via the common receptor, i.e., IL4Rα. However, the myeloid cell-specific role of IL4Rα-mediated signaling in allergic asthma has remained unclear. We hypothesized that myeloid cell-specific IL4Rα signaling is essential for granulocytic inflammation and associated pathological outcomes.

Methods
Myeloid cell-specific IL4Rα-deficient (LysMCRE/CRE/IL4RαFl/Fl) and control (LysMCRE/CRE/IL4RαWT/WT) mice were exposed to mixed allergens, and total and differential cell counts were performed on bronchoalveolar lavage fluid. Unlavaged left lung lobe was fixed in 10% formalin and used for lung pathology assessment.

Results
In contrast to mixed allergen-exposed control mice that had exaggerated immune cell recruitment, myeloid cell-specific IL4Rα-deficient mice had significantly reduced immune cell infiltration into the lung airspaces. The reduction in immune cell infiltration in myeloid cell-specific IL4Rα-deficient mice was attributable to a significant decrease in eosinophils and lymphocytes. Additionally, while mixed allergen-exposed control mice exhibited pronounced lung inflammation and consolidation, myeloid cell-specific IL4Rα deletion significantly ameliorates lung pathology. Mucous cell metaplasia (MCM), another key feature of allergic asthma, was unaltered in myeloid cell-specific IL4Rα-deficient mice suggesting its dispensable role in mixed allergen-induced MCM.

Conclusion
Collectively, our data show that myeloid cell-specific IL4Rα signaling plays an indispensable role in immune cell recruitment specifically eosinophils, and its deletion protects against mixed allergen-induced lung injury.
Supported by grants from NIEHS (R01 ES030125) and NIGMS (P20 GM130555-6611)
Early life exposure to Streptococcus pneumonia has sex-specific long-term impact on inflammatory responses
Authors: Lauzon-Joset Jean-Francois , Lerdu Ophelie , Bouchard Karine , Patoine Dany , Mbareche Hamza , Bissonnette Elyse 
Published: January 2023

Abstract

INTRODUCTION
Lung microbiota plays a central role in health and disease development. Recently, recurrent viral infections in preschool age children were associated with lung microbiota carriage of Streptococcus pneumonia (SP). In addition, immune development and inflammatory responses have sexual dimorphism, but it is still controversial whether there is sex-specific microbiota composition.

OBJECTVE
Given that immune development occurs early in life, the objective of this project is to evaluate the consequences of early life lung microbiota alteration by SP exposure on inflammatory response later in life.

METHODS
Neonatal Brown Norway rats were exposed to SP via intranasal administration (sub inflammatory dose). Lung microbiota was assessed until weaning age (21 days old), using v3–v4 16S rRNA sequencing. At 8 weeks old (post-puberty), rats were infected with LPS and their inflammatory responses were assessed 24h post using bronchoalveolar lavage (BAL).

RESULTS
Early life exposure to SP reduced lung microbiota diversity and impacted its constitution until weaning age. Although control females exposed to LPS had higher inflammatory response than control males, early life exposure to SP significantly reduced BAL inflammatory cell recruitment in females but not in SP-males. Opposingly, in SP-males, the inflammatory response shifted from a neutrophilic response to a more eosinophilic inflammation.

CONCLUSION
Early life exposure to SP modulated both lung microbiota and immune responses later in life. The sex-specific immune modulation by lung microbiota composition in early life could have large implication for many inflammatory diseases presenting sexual bias.
Supported by grants from Quebec Health Research Network and Fondation IUCPQ (Quebec, Canada).
Immunoresponsive gene 1 modulates neuroinflammation through the induction of heme oxygenase-1
Authors: Kuo Ping-Chang , Weng Wen-Tsan , Scofield Barbara A , Furnas Destin , Paraiso Hallel C , Yu I-Chen , Yen Jui-Hung 
Published: January 2023

Abstract
Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of IRG1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. Currently, whether IRG1/itaconate axis exerts a modulatory effect in ischemic stroke remains unexplored. In this study, we investigated whether IRG1 plays a role in modulating ischemic brain injury. Our results showed IRG1 was highly induced in the ischemic brain following ischemic injury. We found that IRG1−/− stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild type stroke controls. Furthermore, IRG1−/− stroke animals presented aggravated blood-brain barrier disruption, associated with augmented Evans blue leakage of the ischemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86, and Iba1 expression. Further analysis revealed that IRG1 was induced in microglia after ischemic stroke, and deficiency in IRG1 resulted in repressed microglial heme oxygenase-1 (HO-1) expression. Notably, the administration of dimethyl itaconate, an itaconate derivative, to compensate the deficiency of IRG1/itaconate axis led to enhanced microglial HO-1 expression, alleviated ischemic brain injury, improved motor function, and decreased mortality rate in IRG1−/− stroke animals. In summary, we demonstrate that the induction of IRG1 in microglia following ischemic stroke may serve as a protective mechanism to restrain brain injury through HO-1 upregulation.
This work was supported by Indiana University Startup Fund and in part by the National Institutes of Health (R01NS102449) to J.-H.Y.
MEF2A is a Regulator of Interferon-Mediated Inflammation
Authors: Forero Adriana , Smith Julian R , Dowling Jack W , Savan Ram 
Published: January 2023

Abstract
Interferons (IFN) are antiviral cytokines induced by recognition of viral nucleic acids or cellular replicative stress. In particular, the accumulation of cytosolic nucleic acids or the accumulation of DNA lesions has the potential to activate cGAS/STING-mediated IFN induction if not properly constrained. While these responses can be harnessed as tumor therapies, the excessive induction of IFNs and deleterious IFN-mediated inflammation is associated with tissue damage in non-malignant disease. We sought to identify non-canonical IFN-modulatory transcription factors (TF) by examining factors with known genetic alterations that associate with both malignant and inflammatory diseases. Here, we identify MEF2A as a negative regulator of the production of IFNs at homeostasis. The loss of MEF2A function results in the spontaneous induction of type I and III IFNs and downstream ISG expression. We demonstrate that IFN production following MEF2A depletion was dependent on DNA replication and cell cycle progression with CDK2 inhibition ablating this response. Furthermore, DNA lesions that induced DNA damage responses following MEF2A loss resulted in cGAS/STING pathway activation and genetic deletion of STING maintained homeostatic levels of type I IFN in the absence of this TF factor. Thus, our study is first to connect MEF2A with protection from maladaptive type I IFN responses due to genomic instability across various cell types. Overall, our study reveals that therapeutic modulation of MEF2A or other members of its family could be beneficial for the management of viral, malignant, and autoinflammatory diseases.
Myeloid cells regulate retinal neovascularization via SOCS3
Authors: Sun Ye , Wang Tianxi , Lam Enton 
Published: January 2023

Abstract
Neovascularization is the leading cause of vision loss in retinopathy of prematurity (ROP). Inflammation and myeloid cells are involved in retinal angiogenesis. However, the underlying mechanisms of how myeloid cells control neovascularization in ROP remain unknown. We and others previously reported that suppressor of cytokine signaling 3 (SOCS3) is induced in retinopathy. To investigate whether myeloid cells regulate retinal angiogenesis via SOCS3 in ROP, we used myeloid lineage specific SOCS3 loss-of-function (conditional knockout, cKO) mice and gain-of-function (conditional overexpression, cOE) mice and generated ROP mouse model - mice with oxygen induced retinopathy (OIR) by exposing mice to 75% oxygen from postnatal day (P)7 to P12 for 5 days, and then returned to normal air until P17. Retinas were collected for analysis including quantification of retinal neovascularization, gene expression, immune cell profiling and single cell sequencing. Our results showed that mice with myeloid SOCS3 deficiency had a substantial increase in pathological retinal neovascularization, whereas overexpression of SOCS3 in myeloid cells prevented pathological retinal neovascularization in response to OIR. Our single-cell sequencing data showed that population of myeloid lineage cells including microglia, macrophages and neutrophils was changed in mice with OIR and controlled by SOCS3. Therefore, myeloid cells are involved in retinal neovascularization via SOCS3 in ROP. Manipulating SOCS3 expression in myeloid cells may provide a new way to cure neovascularization in retinas.
Supported by grants from NIH (R01EY030140, R01EY029238) and from BrightFocus Foundation
Targeting TCA cycle metabolites by small molecule inhibitors ameliorate LPS induced immune tolerance in Macrophages through epigenetic mechanisms
Authors: Abhimanyu Abhimanyu , Ladki Malik , Longlax Santiago Carrero , Sheikh Daanish , Nishiguchi Tomoki , Dinardo Andrew 
Published: January 2023

Abstract

Background
Severe and chronic infections, such as sepsis and Tuberculosis, result in macrophage immune tolerance in order to prevent pathologic inflammation. Immune tolerance is believed to be a result of metabolic dysregulation, especially of the TCA cycle. Metabolites play a critical role in regulating epigenetic mechanism, but many aspects remain poorly understood.

Methods
An in-vitro LPS tolerance model was used to evaluate if manipulating the TCA cycle could mitigate immune tolerance. Intracellular signaling, DNA methylation, and nuclear localization were measured using RPPA, Illumina EPIC, and confocal microscopy, respectively.

Results
Metabolic inhibitors of glycolysis (metformin), the TCA cycle (BAY 1436032), and mTOR (rapamycin and everolimus) blocked LPS-induced immune tolerance. LPS treatment changed the methylome with hypermethylation of key genes of the TCA cycle including PDP2, NDUFS8, TRAP1 and PDK2 and lead to increased nuclear localization of the TCA enzymes, which could be ameliorated with inhibitors. Increased levels of key mediators of the TCA by LPS treatment including p-mTOR, pAKT, LDHA, IDH1, LC3A and epigenetic regulator p300 was significantly downregulated by pre-treatment with metformin, everolimus and BAY 1436032. BAY 1436032 also significantly reduced the LPS induced upregulation of epigenetic enzymes including histone deacetylases (HDAC) 3,4, and EZH2.

Conclusion
Previous studies demonstrated that LPS induces epigenetic-mediated immune tolerance. Here we show this can be mitigated by inhibiting glycolysis, mTOR pathway and TCA cycle. This could have clinical implications in treatment of sepsis and Tuberculosis among other diseases.
Supported by NIAID K23 AI141681-02
Targeting intrinsic regulators of antibody and B cell memory to control chronic viral infection
Authors: Good-Jacobson Kim , Di Pietro Andrea , Cooper Lucy 
Published: January 2023

Abstract
The production of antibody and formation of immunological memory underpins vaccine success. Yet, chronic viral infections result in an inadequate humoral response, and little is known about the mechanisms underpinning this dysregulation. We therefore utilised acute or chronic strains of lymphocytic choriomeningitis virus (LCMV) to investigate B cell behaviour in vivo during chronic infection. Our work revealed that chronic infection altered epigenetic regulation of B cell fate, and a key epigenetic target could be therapeutically modulated to correct antibody responses. Deep-sequencing revealed key differences in chromatin accessibility of B cells responding to acute vs chronic infection, leading us to investigate the Polycomb repressive complex 1 component BMI-1. BMI-1 was upregulated in germinal centre B cells of mice infected with chronic LCMV, compared to acute LCMV. B cell-intrinsic deletion of BMI-1 resulted in a restoration of splenic architecture, and an enhanced and rapid ability to clear virus. Deletion of BMI-1 re-established appropriate c-Myc expression in B cells, concomitant with improved quality of antibody with enhanced antibody-dependent effector function and increased neutralising capacity. Together, our data defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection. Further, single-cell RNA-seq and genetic models revealed that excess immune complexes, in concert with dysregulated complement-mediated functions, contribute to ineffective memory formation during chronic viral infection. Understanding the molecular events that may sustain dysfunction lays the foundation for improving therapeutic interventions in chronic infectious diseases.
Supported by Bellberry-Viertel Senior Medical Research Fellowship and an AAI Careers in Immunology Fellowship.
Blimp1 controls GC B cell expansion and exit through regulating cell cycle progression and key transcription factors BCL6 and IRF4
Authors: Luo Wei , Conter Laura , Callahan Derrick , Smita Shuchi , Shlomchik Mark J 
Published: January 2023

Abstract
Blimp1 is required for plasma cell differentiation and antibody production. Blimp1 is also expressed in some dark zone germinal center (GC) B cells (GCBC), however, the exact role of Blimp1 in regulating GC B cell function is not clear. To investigate this, we generated chimeric mice using equal mixtures of bone marrow (BM) from Blimp1+/+ CD19Cre and Blimp1fl/fl CD19Cre mice. In these BM chimeras, Blimp1 sufficient and deficient B cells compete in the same environment, allowing us to examine the cell-intrinsic function of Blimp1 in GCBC, independent of environmental factors such as antibody or antigen levels. We discovered striking B cell-intrinsic roles for Blimp1. Blimp1 deficient B cells quickly dominate GCs and persist for a much longer time compared to the wild type cells. Mechanistically, Blimp1 deficiency increases the percentage of GCBC in the S phase. This difference seems independent of positive selection signals, because Blimp1 deficient GCBC express normal levels of c-Myc, a marker of positive selection. Importantly, Blimp1 deficient GCBC fail to downregulate BCL6 and upregulate IRF4, suggesting that Blimp1 induction in GCBC controls the expression of these key transcription factors, which are required for exit from the GC program. Consistent with this, memory B cells derived from the Blimp1 deficient B cells were only slightly increased, despite the fact that Blimp1 deficient GCBC are highly expanded and persistent. In addition, Blimp1 deficiency also reduced class-switching to IgG1 in response to NP-CGG immunization. These findings revealed unique antibody- and antigen-independent functions of Blimp1 in regulating GCBC responses that impact long-lived immune compartments.
Inverse-agonist (SMM-189) suppresses colitis by inducing endogenous cannabinoids and attenuating Th17, neutrophils, natural killer cells
Authors: Rakib Ahmed , Kiran Sonia , Boddu Geetha , Moore Bob M , Singh Udai P 
Published: January 2023

Abstract
The cause of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are multi-factorial and include activated immune cells, chronic inflammation, genetics, and environmental exposure. It is well known that endocannabinoids mediate protection against intestinal inflammation and other autoimmune diseases. However, the effect of cannabinoid receptors induction by inverse-agonist during experimental colitis has not been investigated. Here, we investigate the activation of the cannabinoid receptor-2 (CB2) by SMM-189, a potent CB2 inverse agonist, on the inhibition of dextran sodium sulfate (DSS) induced colitis. In the present study, we found that SMM-189 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis, increased body weight and colon length while increasing the expression of CB2 receptors and protein kinase A (PKA) in the colon lamina propria (LPs). We also measured a decrease in the percentage and number of Th17 cells in the spleen, mesenteric lymph nodes (MLNs), and LPs treated with SMM-189 compared to DSS controls. Similarly, the percentage and number of natural killer T (NKT) cells and neutrophils are decreased after SMM-189 treatment. SMM-189 also induces the myeloid-derived suppressor cells (MDSCs) during chronic colitis progression as compared to DSS alone. These findings suggest that SMM-189 ameliorates experimental colitis by inducing CB2 receptors and PKA in the LPs, MDSCs and reduces Th17, NKT cells, and neutrophils from the spleen and LPs. Taken together, these data support the idea that the CB2 inverse agonists, such as SMM-189, may be developed as a novel therapeutic target for IBD.
Supported by NIH grant R01 AI140405