bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping the timeline of dendritic cell migration and crosstalk in the CNS-lymphatic axis
Authors: Laaker Collin , Hsu Martin , Herbath Melinda , Sandor Matyas , Fabry Zsuzsanna 
Published: February 2023

Abstract
Recent studies show that meningeal lymphatic vessels surrounding the brain are quite reactive during neuroinflammatory disease states and can undergo changes in morphology to regulate the changing CNS microenvironment. It has been shown by our lab that cribriform plate lymphatic endothelial cells (cpLECs) functionally expand, proliferate, and change expressional profile in response to neuroinflammation. This shift in cpLEC phenotype is also associated with an increased affinity for leukocyte interactions, specifically dendritic cells (DCs). We hypothesize that these DC-cpLEC interactions are an important source of these lymphatic cell modifications and thus CNS homeostasis. However, the timing, origin, and full functional impact of peripheral DCs communication with cpLECs is unknown. In this study we attempted to track the arrival of peripherally stained DCs during neuroinflammation as they migrate to a cellular synapse with cpLECs. Utilizing a method of intravascular staining we found that peripherally stained DCs from the blood do not have immediate access to the cribriform lymphatics but can be observed bound to these lymphatic cells as early as 6hrs post injection, with steadily increases populations thereafter. Additionally, we mapped the migration of peripherally stained DCs across CNS parenchyma along key points of migration and infiltration like the choroid plexus, olfactory bulbs, and periventricular areas. Finally using novel methods of transgenic mice with photoconvertible cells, we validate that leukocytes bound to cpLECs have passed through the CNS parenchyma. Together these data attempt to characterize the complete circuit of migratory DCs pathway from the blood and through the CNS-lymphatic network.
STAT2 Deficiency Protects from Acute Colitis by Enhancing IL-22 Signals
Authors: Gamero Ana M , Cremers Tess , Pryimych Nataliya 
Published: February 2023

Abstract
Ulcerative colitis (UC) is one of two major forms of inflammatory bowel disease (IBD). This debilitating chronic condition causes inflammation in the colon and heightens the risk of colorectal cancer. What causes IBD remains largely unclear. Type I and Type III interferons are cytokines that protect from colitis via activation of the ISGF3 transcriptional complex composed of STAT1/STAT2/IRF9. Yet, our previous studies have shown that STAT2 promotes colitis-associated carcinogenesis suggesting that STAT2 may also be implicated in IBD. Therefore, we investigated the role of STAT2 in intestinal inflammation by employing the dextran sodium sulfate (DSS) model of human UC-like acute colitis. DSS-induced Stat2KO mice experienced less body weight loss compared to wild type mice. Pathology scoring of Stat2KO colons revealed reduced damage to the epithelial gut barrier, mild inflammation, and less immune cell infiltration. Conversely, DSS-induced Stat2KO bone marrow chimaeras harboring wild type immune cells developed severe intestinal inflammation indicating a STAT2 mediated immune response. Furthermore, DSS-induced Stat2KO colons showed reduced induction of inflammatory IL6 and Lcn2. In contrast, early induction of the antimicrobial cytokine IL-22 and associated IL-22 target genes was observed together with Stat3 activation in colonic epithelial cells. In addition, IL-22 treatment of Stat2KO colonic epithelial cells led to enhanced STAT3 activation. Therefore, STAT2 is damaging- in part- by attenuating the protective effects of IL-22. Collectively, this bring to the forefront an unrecognized but detrimental role of STAT2 in the pathogenesis of UC, that when deregulated may cause progression to colorectal cancer.
Innate Lymphocytes in Young Splenocytes Promote Protection Against Plasmodium chabaudi Infection
Authors: Opata Michael M. , Smith Margaret Rose , Richard Lyndsay Blake 
Published: February 2023

Abstract
Immunity to malaria requires an elongated time to develop and understanding of the immune response to malaria, especially in children under five, is limited due to the lack of a reliable animal model to study the pathogenesis of the disease. By utilizing a newly developed young rodent model in our lab, we have observed that both splenocytes and purified CD4+ T cells from 8-week adult mice proliferate faster than day 15 old young mice (pups) when stimulated in vitro. Based on the proliferation pattern, we concluded that as the mice age, their cells have the potential to proliferate faster. When transferred to immunocompromised RAG1 knockout (RAG1KO) mice, both pup and adult cells protected from death. This data suggests that there is both a proliferative and responsive cell population in the splenocytes of pups that may promote protection against malaria infection in mice. To better understand this responsive cell population, we adoptively transferred splenocytes from both pups and adult mice into RAG1KO mice and infected the cell recipients with P. chabaudi. We observed higher proportions and numbers of innate lymphocytes including gamma delta (γδ) T cells and natural killer (NK) cells in the pup splenocyte recipients when compared to the adult counterparts on day 9 post-infection. However, there were significantly higher proportions of macrophages in the adult spleen cell recipients. Taken together, our findings suggest that pup cells are enriched with innate lymphocytes that may promote protection against P. chabaudi infection.
The role of intracellular Pattern Recognition Receptors (PRRs) in recognition and immunomodulation of Dendritic cells (DC) in response to Daptomycin (Dap) resistant MRSA
Authors: Jahan Nazneen , Jiang Jhih-Hang , Peleg Anton Y. , O’Keeffe Meredith 
Published: February 2023

Abstract
Methicillin resistant Staphylococcus aureus (MRSA) infection is one of the leading causes of hospital-acquired infections and is more difficult to treat than other bacterial infections. In recent years, resistance to last line anti-staphylococcal antibiotic daptomycin has been observed during treatment of MRSA bacteremia. Protection against MRSA infection is challenging and requires both innate and adaptive immune effector mechanisms. Being at the interface between innate and adaptive immune responses, DCs are thus central to the immune protection against S. aureus. We have previously shown that distinct and paired clinical isolates of MRSA have differential capacity to induce DC activation, with MRSA strains resistant to the last_line antibiotic daptomycin inducing a compromised response to MRSA. However, this study explores the molecular mechanism by which MRSA strains impede DC activation. We explored the role of intracellular PRRs in the recognition and immunomodulation of these clinical isolates. We found that the cytosolic sensors cGAS and STING are implicated in the sensing of clinical isolates of MRSA, but their use is more prominent in response to DapS strains. We also determined that the TLR3 ligand poly(I:C) induced a highly synergistic increase in the activation of DC in response to both Daptomycin sensitive (DapS) and Daptomycin resistant (DapR) MRSA. Our work, thus provides important insights for the mechanism of differential recognition of clinical isolates of MRSA and immunomodulation through engagement of PRR pathways which are critical to achieve effective and comprehensive immune defense against this pathogen.
Bcl3 dependent regulation of Dendritic Cell function in Toxoplasma gondii infection
Authors: Guha June , Kang Byunghyun , Vazquez Estefania , Siebenlist Ulrich , Murphy Philip M 
Published: February 2023

Abstract
The atypical IκB family member Bcl-3 associates with p50/NF-κB1 or p52/NF-κB2 homodimers in nuclei, thereby either positively or negatively modulating transcription in a context-dependent manner. Bcl-3 is critical for host resistance to Toxoplasma gondii and Bcl-3-deficient mice succumbed within 3–5 weeks after infection, correlating with an apparently impaired Th1-type adaptive immune response rather than a defect in the innate immune response. Surprisingly, mice lacking Bcl-3 in CD11c+ dendritic cells (DC) were as susceptible as mice globally deficient for Bcl-3, demonstrating that Bcl-3 is required in these cells to prime protective T-cell-mediated immunity to T. gondii. It remains to be determined however whether conventional or monocyte derived DCs are critical mediators of a successful T cell response against the invading pathogen.
We generated mice specifically lacking Bcl-3 in conventional DCs (Zbtb46 cre knockout [KO]) or in monocyte derived DCs (LysM cre KO). Surprisingly, both conditional KO strains were as susceptible to T. gondii infection as total KO mice. Interestingly, we detected the presence of a unique subpopulation of conventional DCs that expressed the monocytic markers CD64 and Ly6C in infected spleen, which was reduced in the absence of Bcl3. Single cell RNA sequencing was done with infected splenic DCs to understand the developmental regulation of DC across genotypes. Functionally Bcl3 depleted DC are poor presenter of antigen and are defective in cross presenting toxoplasma specific antigens. Consequently, the T cells are poorly primed in these KO mouse leading to inadequate generation of inflammatory cytokines such as IFNg, which is indispensable for host protection.
Microenvironment controls inflammatory response in macrophages
Authors: Zhou Xu , Pope Scott D , Medzhitov Ruslan 
Published: February 2023

Abstract
Inflammatory response often changes tissue environment, such as pH, oxygen level or composition of cells. Sustained deviation in these variables from homeostasis leads to tissue dysfunction and pathology, as collateral damage of inflammation. Meanwhile, we begin to realized that immune cells also constantly monitor tissue environment and maintain tissue homeostasis. This raises an intriguing question: do changes in tissue environment feedback to modulate immune functions during inflammation?
pH is normally maintained within a narrow homeostatic range. Decrease in pH, or known as acidosis, is associated with diverse inflammatory conditions. Using macrophages, we found that acidic pH modulates their inflammatory response to lipopolysaccharide (LPS, TLR4 agonist) in a gene-specific manner, independent of known pH-sensing receptors. Employing a computational deconvolution algorithm, we systemically characterized how change in pH and activation of TLR4 regulate inflammatory gene expression. This revealed three distinct gene classes: a group insensitive to environment, and two groups representing alternative inflammatory programs, whose control by LPS is either antagonistic or synergistic with acidic pH. Surprisingly, this influence by pH correlates with differential control by NF-kB and IRF3, but is not due to difference in pathway activity. Through profiling chromatin landscape, we discovered that pH regulates gene expression via the activity of specific enhancers and chromatin remodeling. Our findings highlight a critical role of tissue microenvironment in controlling inflammatory gene expression, and reveal qualitatively different responses encoded by transcription circuits and epigenetic mechanisms.
IL-33 sensitizes mast cells to respond to a second alarmin, ATP, but not PAMPs.
Authors: Straus David , Pryor Destiny T. , Kee Sydney Ann , Haque Tamara T , Ryan John J 
Published: February 2023

Abstract
Barrier defenses must respond rapidly to pathogen infection but avoid responses to innocuous antigens or microbes. Aberrant recognition can lead to hypersensitivity and/or chronic inflammatory conditions. Barrier tissues actively release alarmins such as IL-33 in response to cell stress helping to identify pathogenic stimuli. Additional alarmin molecules such as ATP, uric acid crystals, and HMBG protein have also been identified but it remains unclear how the innate immune system integrates these multiple signals. We have used mast cells to address how IL-33 and ATP signals interact. While best known for their role in IgE-mediated allergic responses, mast cells readily produce inflammatory cytokines in response to either IL-33 or ATP. Measuring secreted IL-6, TNF alpha and IL-13 we found that bone marrow-derived and peritoneal mast cells had a 3–6-fold increased response to ATP when sensitized by pretreatment with IL-33. This synergistic effect was observed at relatively low ATP concentrations (&lt;300μM) and required &lt;1hr exposure to IL-33. Stimulating with PAMPs (LPS, LTA, poly I:C, ß-glucan) failed to show any enhancement with IL-33 pretreatment. Inhibitor studies indicated that the P2X3 receptor and the NFAT transcription factor mediated the ATP response. To test IL-33 and ATP synergy in vivo, we assessed eosinophil mobilization to the peritoneal cavity in mice. Consistent with the in vitro studies, co-administration of IL-33 and ATP increased eosinophil numbers compared to either alarmin alone. These results support the hypothesis that alarmins collaborate to surpass a threshold level of barrier stress necessary to initiate an inflammatory immune response.
Transcriptional regulation of type 2 innate lymphoid cells and precursors by interleukin-7 receptor signalling
Authors: Lu Julia , Sheikh Abdalla , Abraham Ninan 
Published: February 2023

Abstract
Innate lymphoid cells (ILCs) are a rare population of innate immune cells that act as the first line of defense against pathogens. These cells arise from the lymphoid lineage that B and T cells also belong to. Type 2 ILCs (ILC2s) are a subset of ILCs that reside in the lungs, mucosal layers, and skin, and have roles in clearing helminth infections, triggering allergic responses, and promoting lung tissue repair after influenza infections. The functions of ILC2s mirror those of TH2 cells but lack antigen recognition. However, their full development background is still unknown. It is believed that ILC2s develop in the fetal liver and adult bone marrow from common lymphoid progenitors and differentiate into several intermediates including helper ILC precursors. From this, ILC2 progenitors arise and express interleukin-7 (IL-7) receptor with the aid of the transcription factor GATA3. Our lab has found that IL-7 is critical for ILC2 development as mutations to the IL-7 receptor show a reduction in the ILC2 numbers and GATA3 expression. Conversely, overexpression of IL-7 results in the expansion of ILC2s and elevated GATA3 expression. We hypothesize that IL-7 signalling dictates ILC2 development through the transcriptional regulation of lineage determining factors. We aim to identify the transcriptional and epigenetic landscape regulated by IL-7 in ILC2s and their progenitors using single cell RNA sequencing and chromatin immunoprecipitation sequencing. We will also investigate how IL-7 influences airway immune responses generated by ILC2s using flow cytometry and RNA sequencing. This study will increase our understanding of a vital cell population and contribute to the development of therapeutics for allergic asthma and viral infections.
Postnatal ozone exposure disrupts alveolar development, exaggerates mucoinflammatory responses, and suppresses bacterial clearance in developing Scnn1b-Tg+ mice lungs.
Authors: Choudhary Ishita , Vo Thao , Paudel Kshitiz , Yadav Radha , Mao Yun , Patial Sonika , Saini Yogesh 
Published: February 2023

Abstract
Increased levels of ambient ozone result in the respiratory tract injury and worsening of ongoing lung diseases. However, the effect of ozone exposure on the respiratory tract undergoing active lung development and simultaneously experiencing mucoinflammatory lung diseases such as cystic fibrosis (CF) remains unclear. To address these questions, we exposed sodium channel non-voltage gated 1, beta subunit overexpressing transgenic mice (Scnn1b-Tg+), a mouse model of CF-like lung disease, and littermate wild type (WT) mice to ozone from postnatal day (PND) 3–20 and examined the lung phenotypes at PND21. As compared to filtered air (FA)-exposed WT mice, the ozone-exposed WT mice exhibited marked alveolar space enlargement, significant eosinophilic infiltration, type-2 inflammation, and mucous cell metaplasia. Ozone-exposed Scnn1b-Tg+ mice also exhibited significantly increased alveolar space enlargement, exaggerated granulocytic infiltration, type-2 inflammation, and greater degree of mucoobstruction. The alveolar space enlargement in ozone-exposed WT, and ozone-exposed Scnn1b-Tg+ mice was accompanied by elevated levels of MMP12 protein in macrophages and Mmp12 mRNA in the lung homogenates. Finally, while bacterial burden was largely resolved by PND21 in FA-exposed Scnn1b-Tg+ mice, ozone-exposed Scnn1b-Tg+ mice exhibited compromised bacterial clearance which was also associated with increased levels of IL-10, an immunosuppressive cytokine, and marked mucoobstruction. Taken together, our data show that ozone exposure results in alveolar space remodeling during active phases of lung development and markedly exaggerates the developmental history of an ongoing mucoinflammatory pediatric onset lung disease.
Neutrophils contribute to Doxorubicin-Induced Cardiotoxicity
Authors: Bhagat Anchit , Kleinerman Eugenie S 
Published: February 2023

Abstract
Doxorubicin (Dox) is a widely used chemotherapy agent for treating childhood cancer. However, Dox causes damage to the heart and as a result childhood cancer survivors are at higher risk of developing a cardiovascular disease at an earlier age. Elucidating the mechanisms by which Dox induces cardiotoxicity is crucial to identify therapeutic interventions. The innate immune system, in particular: neutrophils have been linked to several cardiac diseases. However, their role in Dox-induced cardiotoxicity has not been examined. Here, we hypothesize that neutrophils contribute to early damage caused by Dox treatment. We first evaluated whether Dox treatment induced neutrophil infiltration in heart. Mice were treated with Dox for 2 weeks and then neutrophil infiltration was quantified 24 hours after therapy by flow cytometry. There was an increase in neutrophils in heart tissue of Dox-treated mice as compared to controls. Additionally, when heart function was quantified by echocardiography, we found a decrease in ejection fraction [EF] and fractional shortening [FS]), and therefore decreased heart function. Next, we depleted neutrophils using an anti-Ly6G antibody and confirmed depletion in the blood and hearts of Dox-treated mice by flow cytometry. We found that neutrophil depletion prevented Dox-induced decrease in both EF and FS both short (24 hours after therapy) and long term (12 weeks after therapy) in the mice. Together these findings demonstrate that targeting neutrophils is a potential strategy to prevent Dox-induced cardiotoxicity.
Polymorphisms in LILRB-1 affects its ligand interactions
Authors: Azaizeh Bara’ah 
Published: February 2023

Abstract
Leukocyte immunoglobulin-like receptor B-1 (LILRB-1) is an inhibitory receptor of the immunoglobulin super family expressed on a subset of natural killer (NK) cells. LILRB-1 binds a wide range of classical and non-classical MHC class I molecules, and a glycoprotein product of the human cytomegalovirus (HCMV), UL18. UL18 is a structural homolog of MHC class I expressed on the surface of infected cells. The two most distal domains of LILRB-1, denoted as D1 and D2, are the main contributors at the interaction interface of LILRB-1 with its ligands. Four non-synonymous polymorphisms within D1 and D2 domains produce LILRB-1’s natural variants. Interestingly, these variants have shown different expression and binding trends on NK cells and were suggested to affect susceptibility to HCMV infection in a cohort of kidney transplant recipients. Differences in the interaction of different LILRB-1 variants with their ligands such as, classical (HLA-Cw15) and non-classical MHC class I ligands (HLA-G) as well as UL18 have are assessed using a flowcytometry based binding assay and confirmed with functional assays. Our experiments show a trend of tight binding range of most LILRB-1 variants with HLA-G. However, the strength of binding is more variant with other classical MHC class I ligands, showing a constant trend based on the protein introduced by each of the four non-synonymous polymorphisms in different genotypes. Such findings may highlight an evolutionary pressure to maintain a relatively constant interaction of LILRB-1 with HLA-G, which is expressed on fetal trophoblasts to maintain maternal tolerance.
Transcription factors NHR-49/PPARα and HLH-30/TFEB promote host defense in C. elegans via a flavin-containing monooxygenase
Authors: Wani Khursheed A. , Goswamy Debanjan , Taubert Stefan , Ratnappan Ramesh , Ghazi Arjumand , Irazoqui Javier E. 
Published: February 2023

Abstract
During bacterial infection, the host is confronted with multiple overlapping signals that are integrated at the organismal level to produce defensive host responses. How multiple infection signals are sensed by the host and how they elicit the transcription of host defense genes is much less understood at the whole-animal level than at the cellular level. The model organism Caenorhabditis elegans is known to mount transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, but the regulation of such responses is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature. This signature was almost completely abrogated by the deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Further, fmo-2/FMO5 was specifically induced by Gram-positive pathogens and Gram-positive natural microbiota of C. elegans. Moreover, the mechanism of fmo-2/FMO5 induction required the nuclear receptor, NHR-49/PPARα, which induced fmo-2/FMO5 and host defense cell non-autonomously. These findings for the first time reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal that FMOs are important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPARα in C. elegans, with important implications for innate host defense in higher organisms.