bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRIM29 promotes persistence of oncogenic DNA viruses by inhibiting innate immune response
Authors: Zhang Ao , Xing Junji , Zhang Zhiqiang 
Published: January 2023

Abstract
Certain double-stranded DNA (dsDNA) virus such as Epstein-Barr virus (EBV) often infect nasopharyngeal and airway epithelial cells (AECs), which is etiologically linked to nasopharyngeal carcinoma in humans. But the underlying mechanisms remain poorly understood. Here we report that in human AECs, EBV employs TRIM29, a member of TRIM family of proteins, to evade immune attacks by inhibiting innate immune activation. We found that the human AECs selectively express TRIM29 and are highly sensitive to EBV infection in TRIM29 upregulation. Indeed, knockdown of TRIM29 in AECs markedly enhanced type I interferon (IFN-I) production, and in human nasopharyngeal cancer cells resulted in almost complete EBV clearance. We also found TRIM29 was highly induced by cytosolic dsDNA in myeloid dendritic cells (mDCs) to control immune response. In animal models, TRIM29−/− mice showed strong adenovirus clearance in the lung, and resistance to lethal HSV-1 viral infections due to enhanced production of IFN-I. Mechanistically, TRIM29 induced K48-linked ubiquitination of STING, a key adaptor in dsDNA sensing pathway, followed by its rapid degradation, thus effectively shutting down the anti-viral innate immunity in favor of viral persistence. These data demonstrate that EBV and possible other dsDNA viruses use TRIM29 to suppress local innate immunity, and key process in viral persistence and development of nasopharyngeal carcinoma.
Role of Notch signaling in basophils in Type 2 inflammation
Authors: Webb Lauren M , Cubitt Rebecca , Wojno Elia Dion Tait 
Published: January 2023

Abstract
Basophils are rare innate granulocytes, making up just 1% of circulating immune cells. Despite their rarity, basophils expand and contribute to the development of host-protective type 2 inflammation and worm expulsion following infection with Trichuris muris, a murine model of human whipworm. However, the pathways that regulate basophil expansion and function in this setting remain unclear. Previous work has shown that the Notch signaling pathway is important in lymphopoiesis and the function of T helper 2 cells, but little is known about its role in innate immune cells. Here, we have investigated the importance of the Notch signaling pathway in controlling the function of basophils during Type 2 inflammation. We show for the first time that basophils selectively upregulate Notch under Type 2 inflammatory conditions. Further, Notch is required for optimal cytokine production from basophils in response to such damage signals as IL-33. Using mice that selectively lack Notch signaling in basophils, we demonstrate that basophil expansion during T. muris infection depends on Notch signaling. Further, efficient clearance of T. muris also depends on effective Notch signaling in basophils. We are now actively investigating how other facets of basophil function are affected by inhibition of Notch signaling. These findings have wide reaching implications for our understanding of innate cell function in Type 2 immunity and for the potential development of therapeutics aimed at targeting Type 2 inflammation. Given that Notch inhibitors are on their way to the clinic, a clear understanding on their impact on Type 2 effector responses is essential. Our work suggests that these therapies could be re-purposed to control aberrant Type 2 immunity.
IL-33 is required for a protective myeloid cell response to T. gondii infection in the brain
Authors: Still Katherine M. , Thompson Jeremy A. , Batista Samantha J. , O’Brien Carleigh A. , Harris Tajie H. 
Published: January 2023

Abstract
Monocytes can traffic to the brain in response to a variety of CNS insults. During infection with the parasite Toxoplasma gondii, monocyte-derived myeloid cells cluster in areas of free parasite and are required to control infection. While the functions of these cells are being investigated, the mechanisms of their recruitment to the infected brain are largely unknown. In regions of focal inflammation, we observe a loss of brain-resident cells and hypothesize that damage to these cells is an initial step in monocyte recruitment. We are specifically exploring the alarmin IL-33 and its potential for immune amplification upon extracellular release. Although largely characterized in barrier tissues, IL-33 is expressed by oligodendrocytes in the CNS. We find that the absence of IL-33 signaling in infected mice results in decreased expression of ccl2, an important chemokine for monocyte recruitment. Using a CCL2-mcherry reporter mouse line we have visualized that CCL2 production greatly increases upon infection and occurs in areas of resident brain cell loss and inflammation. Aligning with a loss of ccl2 we see a decrease in the number of recruited macrophages in IL-33R knockout mice. Though IL-33 has been connected with Type 2 immune responses, IL-33R knockout mice exhibit functional defects in our model’s Th1-dominated environment of intracellular pathogen killing. Specifically, infiltrating myeloid cells in these mice have a decreased capacity to produce iNOS, which is critical for limiting parasite replication. Thus, infected mice lacking IL-33 signaling have an increase in brain tissue cyst numbers. Together, our results demonstrate the impact of one alarmin, IL-33, on monocyte recruitment and control of T. gondii CNS infection.
Fasciola hepatica Fatty Acid Binding Protein (Fh12) inhibits the activation of murine dendritic cells.
Authors: Ruiz-Jiménez Caleb , Celias Daiana , Silvane Leonardo , Cervi Laura , Espino Ana M. 
Published: January 2023

Abstract
Fasciola hepatica, is a helminth that excretes-secretes different proteins that modulate cells of the immune system, generating anti-inflammatory responses. It has been demonstrated that Fh12 achieves this anti-inflammatory effect by inhibiting the expression of TLR4 induced by LPS in macrophages. Fh12 target the CD14 co-receptor, thus blocking the LPS-CD14 binding, which stop the entire TLR4 activation cascade from the beginning of the LPS-stimuli. Concurrently, Fh12 suppress the phosphorylation of various kinases (p38, JNK and ERK) downstream the TLR4 signaling cascade and induce the activation of macrophages by an alternative pathway. Dendritic cells (DCs) are antigen-presenting cells that play a key role at early phase of innate immunity and that are essential in the development of adaptive immune response. The main objective of the current study was to investigate the effect of Fh12 on the activation of murine DCs matured in the presence of LPS. DCs were isolated from bone marrow of naïve C57BL/6 mice, cultured, differentiated and stimulated in vitro with Fh12 1h prior to stimulation with LPS for 18 hrs. ELISA was used to quantify the amount of a panel of secreted cytokines in culture supernatant. FACS was used to determine the activation of MHCII and co-stimulatory molecules. Results demonstrated that Fh12 significantly inhibits the production of IL-12 and IL-6 and reduced the expression of MHCII and co-stimulatory molecules like CD80 on DCs surface. All assays have a significant P value &lt; 0.05. These results suggest that Fh12 exerts a strong suppressive effect on activation of DC cells, which could have relevant implications in the subsequent development of adaptive immune response to microbial pathogens.
HIV myeloid derived suppressor cells (MDSC) are defective in innate immunity to Mycobacterium bovis BCG
Authors: Garg Ankita , Spector Stephen A 
Published: January 2023

Abstract
Disseminated BCG disease and reduced BCG-specific immunity in HIV infected individuals is often fatal in HIV/TB endemic regions. We previously showed that the immune suppressive CD14+ MDSC expand during in vitro or in vivo HIV-infection. Here we examined the factors responsible for defective anti-BCG immunity associated with HIV MDSC. PBMCs from HIV-uninfected healthy donors were cultured with inactivated HIVBaL. After 5 days CD14+HLA DRhi (DRhi) and HLA DR−/lo (MDSC) cell subsets were sorted by flow cytometry (FACS) and infected with BCG at MOI 5 with or without 25OH or 1,25OH vitamin D (vitD). When infected with BCG, DRhi compared to MDSC produced less IL-10 (p=0.04), and more TNF-α (p=0.02) and IL-1β (p=0.05). FACS analysis showed that MDSC compared to DRhi expressed comparable levels of nVDR (p=0.01), but low levels of CYP27B1 (p=0.003) and cathelicidin (p=0.01). The expression of CD86 on MDSC compared to DRhi in response to BCG was low (p=0.02), and remained low when MDSC were cultured in the presence of 25 OH (p=0.03). The expression of CD86 on BCG infected MDSC was comparable to that of BCG infected DRhi only when cultured in the presence of 1,25OH (p=0.07). Similarly, expression of HLA DR on MDSC compared to DRhi in response to BCG was low (p=0.04) and continued to be low in presence of 25OH (p=0.001). The expression of HLA DR on BCG infected MDSC was comparable to BCG infected DRhi only in the presence of 1,25OH (p=0.43). Finally, intracellular replication of BCG in MDSC isolated from HIV-infected individuals was higher compared to replication in DRhi cells (p=0.02). These findings suggest that the impaired killing of BCG by HIV MDSC is due to their defective vitD-cathelicidin mediated innate anti-mycobacterial activity
The protective role of γδ T cells in neonatal influenza
Authors: Guo Xizhi , Thomas Paul Glyndwr 
Published: January 2023

Abstract
Influenza infection is a continuing worldwide health threat, especially in infants and the elderly. Neonates are highly susceptible to influenza infection, which is often causing hospitalization. γδ T cells are the first T cells to develop during embryogenesis and are a significant component of the neonatal immune system. In the neonatal period, conventional αβ T cell responses are functionally less prominent. Hence, γδ T cells are poised to play a critical role in neonatal infections, however, the specific role of γδ T cells in neonatal influenza infection remains to be elucidated. Using a neonatal mouse model of intranasal influenza infection, we observed the activation and proliferation of γδ T cells within two days after infection. By utilizing Nur77-GFP reporter mice, we demonstrated that the activation of γδ T cells was via the TCR and its downstream signaling. IL-17-producing γδ T cells, rather than IFN-γ-producing cells, dominated in the response. A comparison between wild-type and TCRδ-deficient neonates identified a protective function of γδ T cells in neonates, as reduced weight loss and an increased survival rate were observed in the wild-type compared to knockout animals. In infected lungs, wild-type neonates also had more robust IFN-β production and increased inflammatory cytokine production, especially among the Type 2 cytokines, than the TCRδ-deficient animals. Consistently, more eosinophils infiltrated into the lungs of wild-type neonates. Our findings demonstrate a vital role for γδ T cells in mediating protection during neonatal influenza virus infection via a mechanism which appears to include promotion of a Type 2 immune environment that may provide a new therapeutic target for pediatric influenza treatment.
Central and local adaptations sustain Type I Interferon exhaustion during chronic viral infection
Authors: Jo Yeara , Macal Monica , Dallari Simone , Zuniga Elina 
Published: January 2023

Abstract
During chronic infections, sustained cell adaptation via functional exhaustion has been mostly studied in the adaptive immune compartment but much less is known on how innate immune cells adjust to a persistently infectious milieu. Thus, to understand how innate cells adapt to persistent infections, we studied plasmacytoid dendritic cells (pDCs), which specialize in Type I Interferon (IFN-I) production and often become functionally exhausted in chronic settings. Using a murine chronic viral infection model we demonstrated that pDC IFN-I exhaustion is caused by concerted events at central (bone marrow) and local (spleen) compartments. On one hand, undifferentiated bone marrow pDC progenitors exhibited quantitative and qualitative defects and failed to generate functional pDCs ex vivo. Analysis of transcription and chromatin landscapes via RNA-seq and ATAC-seq revealed that IFN-I signaling pathway was enhanced in bone marrow pDC progenitors. Consistently, IFN-I receptor blockade restored the quantitative (albeit not the qualitative) defects of bone marrow pDC progenitors, which was accompanied by restoration of E2-2, a transcription factor critical for pDC development. On the other hand, splenic pDCs received sustained TLR7 signaling, which promoted their maturation but also rendered them unable to produce IFN-I upon ex vivo TLR re-stimulation or in vivo secondary infection. RNA-seq and ATAC-seq analysis in splenic pDCs revealed significant alterations in multiple pathways and transcriptional regulators that are currently being studied. Our work provides an anatomical, cellular and molecular framework to understand how innate immune exhaustion can be triggered and sustained during a chronic viral infection.
Bradykinin mediates the secretion of coagulation factor VIII by mouse dendritic cells
Authors: Clement Cristina C. , Follenzi Antonia 
Published: January 2023

Abstract
Recent experimental evidences proved that kinins, which are a family of octa- to decapeptides structurally related to bradykinin (BK), have modulatory effects on multiple players of the immune system, including macrophages, dendritic cells (DC), T and B lymphocytes, and induce the activation, proliferation, migration, and effector functions of these cells. To further understand the molecular mechanisms underlying bradykinin mediated activation of DCs, we have employed global proteomics and transcriptomic (mRNA) profiling of mouse DCs activated by BK peptide (RPPGFSPFR). The proteomics profiling was performed using a combination of label-free nanoLC-ESI MS/MS and 2D-DIGE analysis. C57BL/6J wild type mice were treated with: 1) BK, or 2) Captopril, an ACE inhibitor that enhances the endogenous BK, or 3) a combination of both drugs (BK+CAP). Following treatment, the DCs (CD11c+) were purified by immunomagnetic sorting. Comparative Ingenuity Pathway Analysis (IPA) identified the upregulated cellular pathways in the BK/CAP/BK+CAP treated DCs, highlighting molecules involved in the DCs migration/chemotaxis, MHC-I and MHC-II expression, antigen presentation pathways, inflammation and cytokines secretion. Moreover, both the comparative proteomics and the transcriptomic analyses demonstrated the significant upregulation of the coagulation pathway (e.g. coagulation factors V, VII, VIII and PAR2 and PAR3 receptors) in the purified DCs from treated mice. Production of coagulation factors V and VIII by BK-activated DCs was validated by RT-PCR, and by immunofluorescence. Our research highlights novel cellular pathways that regulate the cross-talk between inflammation and coagulation in the bradykinin activated DCs.
Reprogramming of inflammatory monocytes by autophagy modulator LiCl
Authors: Rahtes Allison A , Li Liwu 
Published: January 2023

Abstract
Chronic inflammation is an underlying feature of a variety of highly prevalent diseases such as diabetes, atherosclerosis, inflammatory bowel disease, and cancer. Subclinical endotoxemia has emerged as a common factor correlated with these diseases, potentially contributing to the establishment of chronic inflammation through skewing non-resolving inflammatory monocytes. A better understanding of the underlying mechanisms for the programming of non-resolving inflammatory monocytes may facilitate effective strategies to treat diverse inflammatory diseases. We have observed that subclinical low dose LPS may enable non-resolving inflammatory monocytes through disrupting lysosome fusion and causing accumulation of inflammatory mediators such as p62 and pellino1. Administration of autophagy enhancers such as LiCl can attenuate the effects of low dose LPS, by reducing the levels of pellino1. Together, our data suggest an inhibition of autophagy in response to chronic exposure to subclinical endotoxin. Autophagy is a widely recognized homeostatic cellular process with anti-inflammatory capacity. Further elucidation of the mechanism behind this inhibition may shed light on the link between chronic inflammation and chronic subclinical endotoxin exposure, and provide new avenues for disease treatment.
HECT E3 Ubiquitin ligase Nedd4 is required for anti-fungal innate immune response
Authors: Nuro-Gyina Patrick Kwadwo , Tang Juan , Tang Rong , Zeng Qiuming , Ouyang Song , Guo Hui , Lin Guoxin , Tang Na , Liu Jishi , Zhang Jian 
Published: January 2023

Abstract
Candida albicans is the most common cause of fungal infections in humans, and disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with 45% to 75% mortality rate. The understanding of the host–pathogen interactions and the mechanisms of immune regulation against fungal spread is critical for developing immune-based strategies to combat candidemia. Nedd4 (neuronal precursor cell-expressed developmentally down-regulated 4) is a HECT-type E3 ubiquitin ligase which has been shown to positively regulate T cell activation and proliferation. However, the role of Nedd4 in innate immunity is completely unknown. To elucidate the role of Nedd4 in innate immune response against fungal infection, we generated the mice bearing LoxP-flanked alleles encoding Nedd4 with Rosa26-Cre-ERT2 mice to generate Nedd4fl/flRosa26-Cre-ERT2 mice (called ‘Nedd4CreER mice’ here). We also generated mice deficient for Nedd4 in dendritic cells (DC) (Cd11c Cre.Nedd4f/f) or macrophages (LysM Cre.Nedd4f/f). We found that although Nedd4 might not regulate the signaling via TLRs and Dectin-1, Rosa26-Cre-ERT2 mice treated with tamoxifen or mice deficient for Nedd4 in the myeloid cell lineages (macrophages and dendritic cells) are highly susceptible to systemic C. albicans infection, which correlates with defective pro-inflammatory cytokines in the sera, impaired leukocyte recruitment to the kidneys, defective ROS expression by the granulocytes in the kidneys, and heightened kidney fungal burden. Therefore, our data suggest that Nedd4 expression in the myeloid cells is crucial for C-type lectin receptor (CLR)-mediated innate immune response against systemic C. albicans infection.
Innate immune response in acute lung injury following hemorrhagic shock
Authors: Chu Xiaogang , Subramani Kumar , Warren Marie , Raju Raghavan Pillai 
Published: January 2023

Abstract
Trauma is the major cause of death for Americans under the age of 46 years. Hemorrhagic shock accounts for up to 40% of trauma-related deaths. Hemorrhagic shock evokes an acute, non-specific, systemic inflammatory response syndrome (SIRS) resulting in the damage to multiple organs. Acute lung injury (ALI) is one of the most serious complications in traumatic patients, however, the immunological mechanisms in ALI are still not well understood. Recently studies suggest that mitochondria play an important role in physical injury, leading to the onset of the SIRS. In order to address the mechanistic basis of ALI following hemorrhagic shock, we subjected rats to severe hemorrhage and shock (hemorrhagic injury - HI) or sham procedure and lung tissue was tested. We demonstrate that NLRX1, a mitochondria-targeted protein, that negatively regulates innate immunity and cell death responses, was markedly decreased in HI lung. The decrease of NLRX1 was concomitant with the activation of NF/κB and TBK1 signaling pathways. Lung histochemistry was used to establish pathologic effect on the lung. Significant increases in pulmonary expression of inflammatory signaling molecules IL-6, IL-1β, IL-10, TNF-α and MIP-1α further confirmed HI induced pulmonary inflammation and injury. Our results suggest NLRX1 participate in the pathogenesis of HI related pulmonary diseases and support its important role in the regulation of innate immune response following hemorrhagic shock.
IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis
Authors: Choi Jin Kyeong , Dambuza Ivy M , He Chang , Yu Cheng-Rong , Uche Anita N , Mattapallil Mary J , Caspi Rachel R , Egwuagu Charles E 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35 protein might be an effective Biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE), the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, IL-12p35 induced the expansion of Treg and Bregs in part through the inhibition of IL-6- and/or IL-27-mediated activation of STAT1 and STAT3 pathways, respectively. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel Biologic for treating CNS autoimmune diseases and offers the promise of ex-vivo production of large amounts of Tregs and Bregs for immunotherapy.
An Integrative Bioinformatics Approach Identifies In Vivo Validated Drug Candidates with Novel Mechanisms of Action in Rheumatoid Arthritis
Authors: Noblin Elizabeth S , Daugherty Aaron C , Farrington Carl , Hakim Isaac , Radin Andrew M , Chua Mei-Sze , Rabe Mark , Fernald Guy , Ford Daniel , Sirota Marina , Schaevitz Laura , Radin Andrew A 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is an area of active drug development, with over 100 candidates in clinical trials. However, most act on a small number of immunomodulatory targets. Drug candidates that act through new targets or mechanisms could expand treatment options for RA. We applied a data-driven bioinformatics approach and in vivo screen to identify and test new drug candidates and targets that could form the basis of future drug development in RA.
A computational model of RA was constructed by integrating patient gene expression data, molecular interactions, chemical structures, and clinical drug-disease associations. Candidates were scored based on their predicted efficacy in the computational model. FDA-approved treatments for RA were significantly enriched among the top-ranked candidates. Ten high scoring novel candidates were then screened in the collagen-induced arthritis model of RA in rats. Therapeutic treatment with three candidates significantly reduced ankle size, alleviated limb inflammation, improved joint histopathology, and reduced mobility impairments tracked by a novel digital motion endpoint. These candidates are currently approved for metabolic, allergic, and psychiatric indications, and do not act on common RA therapeutic targets. However, links between known candidate pharmacology and pathological processes in RA suggest hypothetical mechanisms that could contribute to efficacy.
Future studies will inform the druggable targets, pathways, and mechanisms that could contribute to each candidate’s efficacy in RA. The candidates could themselves be modified and optimized to increase efficacy in RA. Novel targets identified in these studies could also be the basis of new drug discovery initiatives.