bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid-derived suppressor cell expansion in patients with trans-arterial chemoembolization history
Authors: Thevenot Paul T , Núñez Kelley , Gonzalez-Rosario Janet , Sandow Tyler , Galliano Gretchen , Wyczechowska Dorota Danuta , Ochoa Augusto C , Cohen Ari 
Published: January 2023

Abstract
Cancer-specific myelopoiesis causes peripheral myeloid cell expansion and accumulation at the tumor. Myeloid-derived factors negatively regulate anti-tumor immunity. Doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) can bridge hepatocellular carcinoma (HCC) patients with low stage tumors to liver transplantation (LTx). Unfortunately, HCC recurrence rates remain high, with 5yr tumor-free survival rates estimated at ~50%. Though myeloid-derived suppressor cell (MDSC) expansion has been associated with tumor progression and recurrence risk, the effect of DEB-TACE on MDSC levels is unclear. We observed DEB-TACE HCC patients with disease progression have elevated TGF-β and IL-6 with increased MDSCs at followup. In this study, we prospectively enrolled LTx-candidate HCC patients undergoing DEB-TACE treatment to track MDSCs before and after DEB-TACE treatment based on de novo (DN) verses prior embolization (PE) history. Blood was collected before and &lt; 30 days after DEB-TACE (100–300μm LC Beads™ mixed with 50–75mg doxorubicin). Analyzed were 18 DN patients and 16 PE patients. Tumor diameter and TGF-β levels prior to treatment were similar. CD33+HLA-DRLOW MDSCs were elevated in PE patients both prior to (p&lt;0.05) and following DEB-TACE (p&lt;0.05), but not the number of prior DEB-TACE treatments or radiological treatment response. PE patients with elevated MDSCs (&gt;10%) had elevated TGF-β levels compared to PE patients with &lt;10% MDSCs (p&lt;0.01). PE patients with &gt;10% MDSC also had elevations in IL-6 (p&lt;0.01) and the HCC-recurrence associated MMP-2 (p&lt;0.05). MDSC expansion and elevated TGF-β in HCC patients with DEB-TACE history may identify patients at high risk of early HCC recurrence following LTx.
Non-oncogenic Acute Viral Infection Reduces Tumor Growth in Hosts with Established Cancer
Authors: Newman Jenna H , Li Shengguo , Chesson Brent , Schenkel Jason M , Silk Ann , Zloza Andrew 
Published: January 2023

Abstract
The ability of the immune system to recognize cancer cells as abnormal and to enact effector activity to destroy such cells is a delicate maneuver dependent upon multiple factors. Cancer patients exhibit higher rates of infection than the general population, prompting the question of whether non-oncogenic acute infections impact the ability of patients to mount an anti-tumor immune response, potentially affecting tumor growth and survival outcomes. To assess this, we challenged C57BL/6 mice with B16-F10 melanoma and A/H1N1/PR8 influenza. Influenza was administered upon development of a palpable tumor. We observed that mice bearing an established melanoma that were infected with influenza exhibited reduced tumor growth as compared to mice bearing melanoma alone. Tissues in tumor-bearing mice were interrogated via flow cytometry and a 9-fold reduction in myeloid-derived suppressor cells (MDSCs) was observed in mice concomitantly bearing melanoma and infected with influenza, relative to that observed in the mice bearing melanoma alone. These findings are in sharp contrast to our previous report of increased cancer incidence in cancer-prone mice infected with influenza prior to tumor emergence. These findings suggest that non-oncogenic acute viral infection may play a dual role (increasing the emergence of immune-controlled cancer but decreasing the progression of established cancer). Further, our findings suggest that viral infection in cancer-bearing hosts can be utilized as an immunotherapy for cancer. Future studies will focus on elucidating both the immune-related and cancer cell-related mechanisms that lead to altered tumor growth and survival outcomes in cancer-bearing hosts in the context of viral infection.
Development of an Ex Vivo 3D Functional Assay for Novel Drug Discoveries
Authors: Murali Vasanth Siruvallur , Danuser Gaudenz , Cobanoglu Murat Can 
Published: January 2023

Abstract
Cancer drug discovery is in crisis since only 5.1% of the total drugs entering Phase 1 clinical trials succeed to approval. A reason for the low success rate in clinical trials lies in the initial steps of drug screening using 2D cell cultures and use of immunocompromised mice. Cancer is not just a malignant outgrowth of cells, rather a complex malignancy where the clinical outcome is determined through crosstalk between the malignant, stromal, and immune cells. Furthermore the extracellular matrix is an integral and dynamic part of this crosstalk; examples include TAMs remodeling the ECM and the ECM in turn determining the invasiveness of the malignant cells. since ECM has been shown to be affected by these cells. Thus, a system needs to be designed that introduces all these factors into a drug discovery platform. My aim is to develop an ex vivo assay with humanized synthetic ECM embedded with patient tumor tissue and co-cultured with stromal cells, fibroblast and immune cells isolated from patient. To validate clinical relevance of this complex environment functional assays would be performed to compare drugs response between patients and patient derived tumor. Drug responses on malignant cells will be assessed by 3D high-resolution imaging and computational image morphometrics. My long term goal is to develop a medium throughput novel drug discovery platform that would be guided by machine learning to identify novel chemical compounds.
How do obesity and related inflammation decrease antibody responses in aging?
Authors: Blomberg Bonnie , Diaz Alain , Romero Maria , Vazquez Thomas , Frasca Daniela 
Published: January 2023

Abstract
Decreases in the immune response with aging, including B lymphocytes and antibody-secreting (ASC), are a major contributor to mortality and morbidity in the elderly with increased infections, cancer and autoimmunity. We have shown that the age-related decrease in B cell function is associated with chronic low-grade inflammation and here show is also associated with an increase in fat, visceral adipose tissue (VAT). Adipocyte-derived molecules may not only recruit immune cells but also contribute to the inflammatory process.
We hypothesize that the VAT is an important generator of inflammatory B (and T) cells which contributes to the dysfunction of the aged immune system. Our data in mice show infiltrating immune cells in the VAT have higher percentages of pro-inflammatory B cells (age-associated B cells, ABC) and less Follicular (FO) B cells than in the spleen. The presence of adipocyte inflammatory chemokines and VAT B cell ligands suggest B cell attraction to the VAT and a mechanism for increased pro-inflammatory B cell subsets there. VAT B cells express higher pro-adipogenic and inflammatory markers, including NF-kB, as compared to splenic B cells, and also secrete IgG2c antibodies, which have been shown to be autoimmune in other studies. We also found that in the presence of an adipocyte-conditioned medium, FO B cells differentiated into ABC. These results are the first to show a direct effect of adipocytes on the generation of pro-inflammatory B cells and should help to determine mechanisms for obesity-and age-related changes in inflammation and the immune system.
Lipocalin2, an innate immune protein, modulates iNOS and arginase-1 in macrophages to promote the anti-inflammatory function
Authors: Patterson Daryllynn C , Ignatowicz Aleksandra P , Samuels Janaiya S , Rayalam Srujana , Shashidharamurthy Rangaiah 
Published: January 2023

Abstract
Lipocalin 2 (Lcn2), an innate immune protein, is known to be dramatically up regulated in various inflammatory disorders including autoimmune arthritis, yet its biological role remains unclear. Recently our studies have shown an increase in the accumulation of macrophages in Lcn2 deficient mice compared to wild type (WT) mice in a serum transfer arthritic mouse model. Thus, indicating that the upregulation of Lcn2 might be necessary for the initiation and further resolution of inflammatory processes. In this study, we have investigated the anti-inflammatory function of Lcn2 using murine mouse macrophages. RAW 264.7 cells treated with INFγ and LPS both exhibited pro-inflammatory phenotype, M1, while cells treated with IL-4 displayed an anti-inflammatory phenotype, M2. To determine the anti-inflammatory effects of Lcn2 an IL-10 ELISA revealed that M2 macrophages in the presence of recombinant Lcn2 (rLcn2) significantly increased the expression of IL-10. In addition, arginase-1 expression was found to be significantly upregulated in M2 polarized macrophages in the presence of rLcn2 while inducible nitric oxide synthase (iNOS) expression was down-regulated in the M1 phenotype. However, RAW 264.7 cells treated with Lcn2 alone did not exert either pro- or anti-inflammatory effect. In conclusion, Lcn2 displays the ability to significantly increase the release of anti-inflammatory cytokine, IL-10, thus promoting the anti-inflammatory properties of M2 macrophages. Collectively, our data suggests a crucial role of Lcn2 in the resolution of arthritic inflammation via macrophage polarization, making it a promising target in designing better therapeutic strategies to control the ongoing inflammation during autoimmune arthritis.
β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares
Authors: Goldberg Emily Lauren , Asher Jennifer L , Molony Ryan , Shaw Albert , Zeiss Caroline , Wang Chao , Morozova-Roche Ludmilla A , Herzog Raimund I , Iwasaki Akiko , Dixit Vishwa Deep 
Published: January 2023

Abstract
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. IL-1β produced by macrophages and neutrophils drives gouty flares that cause joint destruction, intense pain and fever. Small clinical trials have reported that IL-1R antagonists reduced pain in gout patients, but these biologicals are expensive and may compromise immune responses. Moreover, current treatment strategies for gout are limited in efficacy and do not specifically target the NLRP3 inflammasome. NLRP3 activation is regulated by numerous metabolic byproducts. However, metabolites that impact neutrophil inflammasome remain unknown. We identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune-defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal activated macrophages which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in outbred rats fed a ketogenic diet, BHB blocked NLRP3-dependent IL-1β secretion from neutrophils from both mice and humans, irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel is also an anti-inflammatory molecule that may serve as a treatment for gout.
MSP-dependent Ron receptor tyrosine kinase signaling reduces white adipose tissue expansion and suppresses hepatic lipid accumulation through an LXR-dependent pathway in ApoE−/− mice fed a high fat/high cholesterol diet
Authors: Allen Joselyn Natasha , Dey Adwitia , Zhang Jingtao , Zhang Limin , Fraser James , Kennett Mary , Patterson Andrew , Hankey-Giblin Pamela 
Published: January 2023

Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a global burden and the pathogenic mechanism is not well understood. The current study was undertaken to investigate a novel signaling pathway involved in attenuating the progression of NAFLD. To establish the role of Ron receptor signaling in NAFLD, Apolipoprotein E knockout (ApoE KO) and Ron receptor ApoE double knockout (DKO) mice maintained on a high fat/high cholesterol diet (HFHCD) for 18 weeks were evaluated. DKO mice showed increased epididymal white adipose tissue (eWAT) mass and type 2 diabetes. Gene expression profiling revealed that DKO eWAT had increased transcript expression of pro-inflammatory cytokines and hypoxia-regulated genes. 1H NMR analysis of blood serum from the HFHCD-fed animals demonstrated that DKO mice had higher levels of circulating free fatty acids which are known to trigger hepatocellular injury and the development of steatohepatitis. DKO mice demonstrated increased levels of circulating ALT and AST liver enzymes, which are key markers for liver injury. Additionally, livers obtained from DKO mice demonstrated increased hepatic lipid accumulation. Genes involved in fatty acid synthesis (srebp-1c, fas), reverse cholesterol transport (abca1), and bile acid synthesis (cyp7a1) were repressed in DKO mice which are all target genes of the liver X receptor (LXR) pathway. Lxr gene expression was also increased in HFHCD-fed ApoE KO mice. Furthermore, ApoE KO mice showed higher circulating levels of triglycerides. Altogether, Ron receptor signaling attenuates white adipose tissue dysfunction and provides insight into a possible mechanism underlying the ability of Ron to suppress hepatic lipid accumulation in mice challenged with dietary cholesterol.
Myeloid sirtuin 6 deletion delays wound healing in mice by modulating inflammation and macrophage phenotype
Authors: Koo Jeung-Hyun , Lee Youngyi , Yun Seok-Kweon , Park Byung-Hyun , Jang Hyun-Young 
Published: January 2023

Abstract
It has been reported that loss of sirtuin 6 (Sirt6) in skin wounds exhibit impaired healing. Given the heterogeneity of macrophage phenotypes during wound repair and the regulation of macrophage phenotypes by sirtuins, we here hypothesized that Sirt6 deletion in myeloid cells would affect macrophages phenotypes in skin wounds and delay wound closure. To address this question, floxed Sirt6 mice were bred with lysozyme M-Cre mice to generate myeloid Sirt6 knockout mice with reduced Sirt6 expression. A full-thickness excisional lesion was made on the dorsal skin of the mice. Compared with wild type mice, wound closure was delayed in KO mice with less collagen deposition, attenuated vWF expression and reduced expression of wound healing related genes. Using immunohistochemistry and RNA expression analyses on macrophage subpopulations from wound tissues, we identified an increased infiltration of M1 type macrophages in KO mice compared with wild type mice. Consistent with the in vivo defects in wound closure, the in vitro study demonstrated that keratinocytes and fibroblasts treated with KO macrophage conditioned medium migrated slower than those of wild type. These results suggest that an imbalance of macrophage phenotypes by Sirt6 deletion contributes to impaired wound healing in mice.
Circadian rhythm disruption promotes alcohol-induced liver and brain injury.
Authors: Fey Holger , Vogle Alyx , Grumish Eve , Dodiya Hemraj , Voigt Robin , Aloman Costica 
Published: January 2023

Abstract
Alcoholic liver disease (ALD) progression to cirrhosis and development of hepatic encephalopathy (HE) are characterized by hepatic and brain inflammation involving innate immune cells. Identifying the risk factors and immune mechanisms involved in susceptibility to liver and brain injury are significant unmet needs. Circadian rhythm disruption promotes alcohol-induced liver pathology. We aim to investigate whether circadian rhythm disruption also primes brain inflammation by impacting trafficking and inflammatory potential of recruited and resident mononuclear phagocytes (MP).
Alcohol (EtOH) is delivered to C57BL/6 mice per a modified NIAAA model of alcoholic liver disease whereby chronic alcohol consumption (20% EtOH v/v in drinking water, 4 wks (Meadows-Cook diet)) is combined with three once daily binges of alcohol. Tissue was assessed via H&E and IHC for α-smooth muscle actin (αSMA) and collagen I (Col I) (liver) and allograft inflammatory factor 1 (Iba-1) (brain). All features associated with human alcoholic liver injury including steatosis, hepatic inflammation and early fibrogenesis were present. Brain mononuclear phagocytes analysed by flow cytometry revealed an increase in recruited and resident MP in response to the alcohol treatment. Moreover, in the steady-state, hepatic and brain MP populations demonstrate circadian oscillations.
Thus, circadian rhythm disruption may modulate alcohol-induced alterations in mononuclear phagocyte trafficking and function similarly in brain and liver.
Cardiac fibroblast participates as an immune modulator in IL-17A-driven post-injury cardiac inflammation and remodeling
Authors: Chen Guobao , Wu Lei , Bracamonte-Baran William , Hou Xuezhou , Diny Nicola , Talor Monica , Cihakova Daniela 
Published: January 2023

Abstract
Heart diseases are the leading causes of mortality and morbidity worldwide. The post-injury cardiac inflammation and remodeling process determined the severity of cardiac damage and the likelihood of developing heart failure. We have adapted both experimental autoimmune myocarditis (EAM) and myocardial infarction (MI) mouse model to investigate the mechanism behind cardiac inflammation and remodeling. We showed that Interleukin 17 (IL-17A) signaling is required for adverse cardiac remodeling and fibrosis in both EAM and MI models. IL-17A induces cardiac fibroblast (CF) to produce granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF in turn drives the development of adverse cardiac remodeling and fibrosis. Despite the heterogeneity of CF population, we successfully identified a specific subset of cardiac fibroblast to be the main recipient of IL-17A signal to produce GM-CSF, CCL2 and other cytokines/chemokines. The same CF subset was detected in heart failure patient biopsies from various etiologies including myocarditis, ischemia patients, etc. Further investigation also revealed that this subset is plastic in cytokine production. Lastly, both complete knockout of IL-17A receptor (R) and specific ablation of IL-17RA in this subset significantly reduced ventricular dilation and infarct scar size. Our findings provide an excellent opportunity to develop specific treatment for post-injury cardiac remodeling and fibrosis through specific targeting the IL-17A signaling to this CF subset or the downstream cytokine production by these cells.
Functional characterization of IRF5 exon 6 variants in SLE risk
Authors: Ozarkar Snehal , McFarland Adelle , Savan Ram 
Published: January 2023

Abstract
The goal of the proposed research is to determine how the interferon regulatory factor 5(IRF5) lupus risk variant translates into biological risk of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified IRF5 as one of the most strongly associated genes with susceptibility to SLE. Although the genetic association of IRF5 with lupus is clear, the exact mechanism by which IRF5 risk variant promotes susceptibility for lupus is still unknown. We are investigating negative regulatory factors of IRF5 activity under normal conditions, which are unable to regulate IRF5 exon 6 risk variants thereby activating type I IFNs leading to aberrant immune activation. We have characterized IRF5 exon 6 variants in pDCs using molecular and biochemical approaches, and investigated the effect of negative regulators on IRF5 exon 6 variants. This will be a significant step to gain the mechanistic understanding of aberrant production type I IFNs and immune activation in lupus.
Increased NCR negative ILC 3 may be indicative for the early development of spontaneous colitis in the IL 10 knockout mouse
Authors: Glover Sarah C , Tang Ying , Li Jian , Doty Andria , Pope Jillian , Yang Ye , Jobin Christian 
Published: January 2023

Abstract
The IL10 knockout (KO) mouse is a model for environmentally and genetically triggered spontaneous colitis. The response of the adaptive immune system to these changes has been studied extensively in this model. However, the response of the innate immune system, specifically the response of innate lymphoid cell (ILCs) populations to the genetic background of the mouse and the environmental stimulus of introducing microbiota has not been well studied. Herein, we evaluated the response of ILCs and Lin marker positive lymphocytes to changes in genotype (wild type Mice B6 in SPF to IL10 KO B6 mice in SPF) and also compared IL10KO mice who were either germ free or SPF exposed. To accomplish this, IL10 knockout mice were exposed to SPF conditions for three weeks. LPMCs were isolated from the colon and small bowel. Innate lymphoid cells were identified as Lin− CD90.2+CD127+cells, and within total ILC, ILC2s were ST2+ cells, ILC1s were ST2−CD117− cells, and ILC3s were ST2−CD117+NKp46+/−cells. As expected, we saw a less developed adaptive immune response in GF IL10 KO mice, with up regulation in this compartment following SPF exposure (Lin+ population increase 1.87 fold). Upon comparison of WT SPF versus IL10 KO SPF, we observed a 5 fold increase in total ILCs and an 18% increase in NCR-ILC3 in the SPF. Comparison of IL10 KO GF versus SPF revealed a 1.8 fold increase in total ILC and a 3% increase in NCR-ILC3s. In conclusion, we show that both genetic and environmental factors play a role in the innate immune changes that occur prior to the development of spontaneous colitis in the IL10 KO mouse and that the shift towards NCR-ILC 3 maybe an early marker for the development of spontaneous colitis.
TLR7 enhances cross-presentation in Ly6C(+) monocytes by targeting endosomal properties.
Authors: Larson Sandy R , Atif Shaikh M , Jakubzick Claudia , Henson Peter M 
Published: January 2023

Abstract
Effector functions of monocytes beyond terminal differentiation has recently come to light. In the present study we have made the novel discovery that Ly6C(+) monocytes can acquire cell-associated Ag from apoptotic cells, termed as efferocytosis. This property was enhanced by the presence of pathogenic stimuli (TLR ligands) directly acting on monocytes. Furthermore, we have shown that monocytes can cross-present Ag acquired from those apoptotic cells, with differential ability of TLR4 and TLR7 ligands in enhancing that process. This has led us to investigate the role of various pathogenic stimuli beyond these two ligands. Our data has confirmed our previous findings and further established the fact that among known TLR ligands, TLR7 selectively enhanced the presentation of peptides on MHC-I molecules. To elucidate the mechanism, we performed RNA sequencing on monocytes treated with a TLR7 ligand showing the involvement of endosomal proteins in antigen presentation, specifically subunits of the NADPH oxidase. Our data clearly demonstrated the role of Ncf-1 in TLR7 mediated enhanced activation of antigen specific CD8+ T cells. Overall, this study defines a unique role for Ly6C(+) monocytes in promoting immunity against single-stranded virus by regulating endosomal pH, a characterized process required for Batf3-dependent DC cross-presentation.