bluuebunny/crossref_metadata_2025_split huggingface dataset:
CpG-A and CpG-B oligonucleotides differentially regulate MR1-mediated microbial Ag presentation
Authors: Liu Jianyun , Brutkiewicz Randy , Liu Sheng , Wan Jun 
Published: January 2023

Abstract
Mucosal-associated invariant T (MAIT) cells are conserved innate T cells that express a semi-invariant T cell receptor (TCR; Vα7.2 in human and Vα19 in mice). MAIT cells are activated by microbial Ags presented by the major histocompatibility complex (MHC)-related molecule, MR1. Little is known how MR1 molecules are processed and loaded with microbial Ag in APCs. We have previously found that Toll-like Receptor 9 (TLR9) is important in regulating MR1-mediated bacterial Ag presentation to MAIT cells in B cells. We further demonstrated that, similar to human B cells, CpG-A (but not CpG-B) upregulated MR1 expression on mouse B cells as well. CpG-A treatment increased MR1 expression on WT mouse B cells but not MR1 KO B cells, further confirming that activation of B cells by CpG-A specifically enhances MR1 surface expression. Initial RNAseq analysis has indicated that B cells activated by CpG-A are distinctively different from those activated by CpG-B or the vehicle control. In conclusion, CpG-A and CpG-B differentially impact MR1 expression and microbial Ag presentation. We have successfully deleted the expression of TLR9 and its downstream mediators in a human B lymphoblastoid cell line (B-LCL) using CRISPR technology. Future work will focus on how genes altered by the activation of CpG-A (but not CpG-B) regulate MR1-mediated microbial Ag presentation.
Depletion of embryonic macrophages impairs vascular development in the murine neonatal small intestine and increases mortality in an experimental model of Necrotizing Enterocolitis
Authors: Managlia Elizabeth , Yan Xiaocai , De Plaen Isabelle G 
Published: January 2023

Abstract
Necrotizing enterocolitis (NEC) is a devastating disease common in premature infants. We previously found that the Cx3cr1+ population and the microvasculature were disrupted in the small intestine (SI) of pups subjected to an experimental NEC model. In neonates, embryonic macrophages (Mφ) dominate the SI Cx3cr1+ population while the adult SI Mφ population expands at weaning to include bone marrow derived-Mφ. Here, we investigated the Cx3cr1+ population in the neonatal (24hr) SI and evaluated its role in vascular development and NEC. We confirmed the Cx3cr1+ population was predominately embryonic by performing flow cytometry on the Lamina Propria (LP) of pups compared to adults using the recently described CD11b+CD64+Tim4+ embryonic phenotype (67.67±8.6 vs 28.35±1.44; p≤0.05). Subsequently, we isolated Cx3cr1+ cells and used real time RT-PCR to establish greater expression of the embryonic-associated genes Tim4 (0.74±0.19 vs 0.22±0.09; p≤0.05), IGF-1 (0.69±0.13 vs 0.26±0.14; p≤0.05) and Lyve (0.49±0.1 vs 0.04±0.02; p≤0.01) in the Cx3cr1+ LP population of neonates compared to adults, while monocyte-expressed L-selectin was heightened in the adult Cx3cr1+ LP population (0.91±0.24 vs 3.2±1.1; p≤0.05). We next found that isolated neonatal SI CD31+ endothelial cells formed tubules on matrigel when co-cultured with Cx3cr1+ cells from the neonatal SI but not from the adult. Finally, in utero depletion of embryonic Mφ via anti-CD115 antibody injection at E6.5, resulted in disorganized vasculature and increased susceptibility to NEC mortality. These data show that the embryonic Cx3cr1+ population plays a role in the development of the SI vasculature and that disrupting this compartment enhances NEC.
Mapping the generation and fate of Tregs associated with recovery of Autoimmune Disease
Authors: Lee Darren J , Muhammad Fauziyya 
Published: January 2023

Abstract
Experimental autoimmune uveitis (EAU) is used to gain a better understanding of human autoimmune uveitis. Resolution of EAU is in part due to emergence of ocular antigen specific regulatory T cells (Post-EAU Tregs) that are found in the spleen of post-EAU mice. However, the stability of these cells and in what tissues these cells migrate to suppress disease is not known. Therefore, we assessed the stability of post-EAU Tregs, asked where these cells migrate to suppress disease, and determined when and where they emerge during EAU. FoxP3GFP-Cre; Rosa26stopfl/fl-Tom mice were used to identify FoxP3 and exFoxP3 T cells. Post-EAU FoxP3 or exFoxP3 cells were adoptively transferred into recipient EAU mice. The post-EAU exFoxP3 cells did not suppress EAU in the recipient mice, but Tregs capable of suppressing uveitis had stable FoxP3 expression and were found in both the eye and lymphoid tissues at the onset of EAU in recipient mice. In donor mice, both FoxP3 and exFoxP3 cells emerged in the eye and were found in the lymphoid tissues throughout EAU. In contrast, neither FoxP3 nor exFoxP3 T cells were found in the eyes of post-EAU mice, rather were found in lymphoid tissues alone. This study elucidates a dynamic relationship of Treg migration from the eye to secondary lymphoid tissues that coincides with the resolution of EAU. Also, this study highlights that FoxP3 is a requirement for the suppressive function of post-EAU Tregs, and these Tregs traffic to the eye to prevent a uveitic relapse but migrate out after resolution. This work suggests that unstable FoxP3 expression or aberrant tissue trafficking may provide an explanation for chronic and relapsing autoimmune uveitis.
Osteopontin promotes survival of intestinal intraepithelial lymphocytes and protects against colitis
Authors: Nazmi Ali , Greer Michael J. , Hoek Kristen L. , Piazuelo M. Blanca , Weitkamp Joern-Hendrik , Olivares-Villagomez Danyvid 
Published: January 2023

Abstract
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells that reside in the epithelium at the interface between the contents of the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes ranging from pathogen control to tissue stability. However, maintenance of IEL homeostasis is incompletely understood. In this report, we present evidence that osteopontin, a glycophosphoprotein with diverse roles in biomineralization, cell-mediated immunity, and inflammation, is important for maintaining normal levels of IEL. Mice in which the osteopontin gene (Spp-1) is disrupted present decreased levels of IEL subtypes, such as TCRαβ and TCRγδ IEL in the intestine, an effect not observed for lymphocytes in other immune compartments such as spleen or lamina propria, indicating an epithelium-specific effect. In vitro experiments show that mouse and human IEL survival is improved by culture with recombinant osteopontin. In vivo and in vitro IEL survival studies show that CD44, a ligand for osteopontin, is critical for the capacity of osteopontin to promote IEL survival. Adoptive transfer of total T cells (including Tregs) from wild type mice into Spp-1−/−Rag-2−/− mice results in the development of exacerbated intestinal inflammation, as compared with Rag-2−/− recipient mice. Further analyses show that osteopontin-deficiency results in decreased survival of Foxp3-expressing T cells. These findings support osteopontin’s critical role in IEL homeostasis and make it a potential target for curbing intestinal inflammation.
Short-term antibiotic treatment immediately after weaning prevents spontaneous ileocolitis
Authors: De Ciantis Christopher L , Jeschke Jonathan C , Hadiono Matthew A , Ziegelbauer Jennifer , Singh Selina , Suchi Mariko , Salzman Nita H , Williams Calvin B 
Published: January 2023

Abstract
A spontaneous model of ileocolitis, a condition found in a majority of cases of Crohn’s Disease, allows for the study of processes that promote homeostasis within the ileum. Our system uses a “Bigenic” approach that combines TCR transgene mice with a transgenic line expressing the cognate antigen in ileal crypts. Bigenic mice exhibit decreased nTreg production that predisposes them to developing a chronic ileocolitic inflammatory disease in the weeks after weaning. Half of Bigenic mice accumulate ileal-reactive Treg cells and fail to develop colitis. In contrast, Ifng−/− Bigenic mice are unable to establish this homeostatic state, resulting in a fully penetrant and acute colitis. We aimed to identify time sensitive interventions capable of preventing colitis and restoring mucosal homeostasis in Ifng−/− Bigenic mice. Mice were started at weaning on a prophylactic treatment with ad libidum non-absorbable antibiotics in their drinking water and continued for three weeks. Alternately, mice were allowed to naturally progress into a disease state at which time the same antibiotic treatments were initiated and continued for nine weeks. We found that antibiotics prevented ileocolitic disease when initiated at weaning but were insufficient to reverse established disease measured by weight loss. Interestingly, this resistance to ileocolitis mediated by short-term early use of antibiotics was maintained, as these mice did not subsequently manifest either ileocolitis or the degree of breakthrough weight loss observed in antibiotic-rescued mice. Our findings suggest that in our model of ilieocolitis, there is a critical window of time after weaning where manipulation of the microbiome alone can facilitate resistance to spontaneous disease.
Targeting gut inflammation inhibits alcohol-induced liver disease
Authors: Deng Zhongbin , Chu Shenghui , Gu Xuemei , Liu Min 
Published: January 2023

Abstract
Alcoholic liver disease (ALD) is one of the leading causes of liver diseases and liver-related death worldwide, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during alcohol intake and is a functional regulator of alcohol-related liver injury that can be exploited therapeutically. Alcohol intake induces a chronic phenotypic pro-inflammatory shift in immune cell populations in gut lamina propria and results in the disruption of intestinal barrier. Treatment of wild-type C57BL/6 mice with the local gut anti-inflammatory, mesalamine, decreases alcohol-induced liver injury, reverses gut inflammation and improves metabolic parameters. Mesalamine reduced gut permeability and endotoxemia, increased IgA secretion and is associated with reduced Akt activation and P-b-catenin levels in the ileum and large intestine. These beneficial effects are dependent on adaptive and gut immunity. Thus, targeting gut inflammation with mesalamine represents a novel treatment approach for alcoholic liver disease.
Lingo3 interacts with TFF2 to control mucosal integrity, Type 1 inflammation, and colitic tissue repair
Authors: Zullo Kelly , Ji Yingbiao , Wei Yun , Herbine Karl , Maloney Nicole , Cohen Rachel , Pastore Christopher , Somsouk Ma , Srivatsa Sriram , Hung Li-Yin , Kohanski Michael , Cohen Noam , Herbert De’Broski 
Published: January 2023

Abstract
Constant exposure of intestinal epithelial cells (IEC) to potentially damaging stimuli makes mucosal repair programs essential for gut homeostasis, immunological quiescence and resistance to colitis. Trefoil factor 2 (TFF2) is a mucus associated protein that promotes epithelial barrier integrity in the lung and intestine, but whether a bona-fide TFF2 receptor exists remains controversial. Herein, we provide evidence that leucine rich repeat nogo interacting protein 3 (LINGO3) is a transmembrane component of TFF2 signaling and proliferation within IEC. TFF2 requires LINGO3 for barrier recovery in scratch-wound assays and mice lacking LINGO3 (LINGO3KO) have impaired intestinal barrier function under steady state conditions. Interestingly, LINGO3KO mice phenocopy TFF2KO mice, with both having a significant accumulation of mucosal CD4+TH1 cells expressing IFNg+ TNFa+ under steady-state conditions and impaired recovery from DSS-induced colitis. Impaired recovery in LINGO3KO animals was marked by reduced intestinal crypt regeneration and reduced expression of the stem cell marker LGR5 compared to WT counterparts. Additionally, TFF2 agonist administration (TFF2-Fc) promoted enhanced recovery and limited inflammatory cell recruitment in WT mice during DSS-induced colitis whereas TFF2-Fc treatment was ineffective in LINGO3KO animals. Combined, these data support our contention that a TFF2-LINGO3 ligand/receptor axis regulates tissue repair and inflammation within the gastrointestinal tract through regulation of IEC function.
Human neural stem cells induce central nervous system specific regulatory T cells from the ex Treg pool and promote repair in models of multiple sclerosis
Authors: Greilach Scott A , McIntyre Laura L. , Hasselmann Jonathan , Othy Shivashankar , Nguyen Quy , Kessenbrock Kai , Cahalan Michael D , Blurton-Jones Mathew , Lane Thomas , Walsh Craig M 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS) and for which there is no cure. Current treatments focus on suppression of the immune system but fail to repair the resulting damage to the CNS. Neural stem cell (NSC) transplantation is a promising therapeutic strategy for treating neurodegenerative diseases through cell replacement and repair however it is unclear how these cells would mediate repair in MS. We report that human NSCs promote CNS specific T regulatory cells (Tregs) which activate endogenous repair pathways and promote remyelination in a murine model of MS. We observed remyelination, decreased inflammation and an increase in (CNS)-infiltrating CD4+CD25+FoxP3+ Tregs in EAE mice receiving an intra-spinal transplant of NSCs. Recovery was not a result of cell replacement, as NSCs underwent xenograft rejection, and was Treg dependent, as ablation of Tregs abrogated histopathological improvement. RAG2−/−2D2 (R2D2) mice, which bear a TCR repertoire restricted to myelin oligodendrocyte glycoprotein (MOG) and neurofilament, lack CD25+FoxP3+ Tregs under homeostatic conditions; however, upon exposure to MOG, R2D2 mice developed CD25+FoxP3+ Tregs in cervical lymph nodes and the spinal cord. hNSCs also promoted Tregs in vitro in co-cultures with wild type B6 and R2D2 splenocytes, but not with RAG2−/− OT-II+ splenocytes. Additionally, hNSC-Tregs also appear to derive from the exTreg pool suggesting both antigen specific expansion and antigen dependent maintenance of FOXP3 in CNS-specific Tregs. hNSC Tregs also have a unique expression profile and express transglutimase-2 which is implicated in oligodendrocyte dependent repair in the CNS.
Non-redundant requirement for CXCR3 signaling for effective treatment of CNS autoimmunity with type I interferon
Authors: Chen Jun , Chong Wai Po , Wang WeiWei , Li Chunmei , Gery Igal , Caspi Rachel R 
Published: January 2023

Abstract
Type I interferons (IFNs) have shown therapeutic potential in treating CNS autoimmune diseases (IFN-β for multiple sclerosis and IFN-α for uveitis), but treatment is not always effective. Here, we describe a non-redundant requirement for GαI-coupled CXCR3 in the immunomodulatory actions of type I IFNs that culminates in the suppression of human uveitis and experimental autoimmune uveitis (EAU). Effective treatment with IFN-α/β inhibited autopathogenic CD4+ T cell migration to effector sites in mice by upregulating expression of the cognate ligands CXCL9, CXCL10 and CXCL11, causing ligand-mediated downregulation of CXCR3 expression and effector T cell retention in the spleen. These effects of IFN-α/β also required IFN-γ. In the absence of CXCR3, type I IFNs were ineffective in treating active EAU. In patients with uveitis, disease exacerbations associated with reduced serum IFN-α concentrations. Importantly, IFN-α/β reduced CXCR3 expression and human effector T cell migration, and these parameters markedly associated with IFN-α therapeutic efficacy in uveitis patients. Our findings provide new insights into the molecular basis of type I IFN therapy for CNS autoimmune diseases and identify CXCR3 as a critical biomarker for effective immunotherapy with type I IFNs.
Antitumor effect of metformin: what about Burkett’s lymphoma?
Authors: Wan Xiaochun , Zhang Guizhong , Huang Shiran , Liu Zhao , Liu Lvyan , Lu Zhen , Tang Chao 
Published: January 2023

Abstract
Metformin, the first-line drug in the treatment of type 2 diabetes, has been reported to possess antitumor activity. However, the roles and detailed mechanisms of metformin in Burkett’s lymphoma are unclear, though it has been suggested to act, at least partially, by mitochondrial complex I inhibition in several tumors. Here, we show that metformin promotes cell death of Burkett’s lymphoma cells but has no effect on the survival of healthy human PBMCs. The pro-apoptotic activity of metformin does not depend on AMPK activation and ROS generation because neither inhibition of AMPK by Dorsomorphin nor scavenging ROS by NAC can block metformin-induced cell death. Moreover, metformin impairs mitochondrial function and induces mitophagy. However, inhibition of the autophagic process by 3-MA promotes the death of these cells, indicating that mitophagy may be a protective factor in cell survival after metformin treatment. Overall, metformin induces cell death via an AMPK- and ROS-independent, mitochondria-mediated manner, which provides new insights into the mechanism of metformin’s antitumor function and suggests that metformin represents a promising and attractive agent for Burkett’s lymphoma therapy.
The role of nano-particulate carbon black in lung cancer development
Authors: Chang Cheng-Yen , You Ran , Kheradmand Farrah 
Published: January 2023

Abstract
Chronic inflammation induced by inhalation of airborne contaminants can contribute to cancer development. We have found that the anthracotic pigment in lungs of smokers is composed of nano-particulate carbon black (nCB), which accumulates in the antigen presenting cells (APCs) and promotes inflammation. Other occupational nCB exposures, such as coal-mining and carbon-black manufacturing, also raise the risk of chronic inflammatory lung diseases. No direct evidence establishes that nCB is a carcinogen; however, several cohort studies have shown a strong correlation between lung inflammation in carbon black industry workers and cancer. We examined whether nCB can promote non-small cell lung cancer (NSCLC) development. Using a novel non-Kras model of NSCLC, in which mice have airway epithelia-specific deletion of tumor suppressors Pten and Smad4 (Ptsd/d), we have found that intranasal challenge with nCB accelerates NSCLC progression. nCB exposure results in myeloid-derived suppressor recruitment and lactate accumulation to paralyze anti-tumor effects. Further, adoptive transfer of APCs from nCB exposed wild type mice (nCB-APC) to Ptsd/d mice showed increased incidences of lung tumor and metastasis, indicating a critical role for APCs in NSCLC progression. nCB-APC-induced immune suppression is in part mediated by expression of immunosuppressive enzymes and lactate production. Additionally, nCB-APCs express both pro-inflammatory and immunosuppressive cytokines to promote tumor growth. These findings suggest that nCB-APCs foster an immunosuppressive microenvironment, and indicate a mechanism responsible for environmental and occupational exposure to nCB in accelerating NSCLC progression.
CD146 contributes the metastatic properties and antitumor immunity of human colon adenocarcinoma cells
Authors: Kato Kazunori , Shimizu Yui , Yamazaki Takumi 
Published: January 2023

Abstract
CD146 (MCAM) expressed on not only vascular endothelial and smooth muscle cells but also various malignant tumor cells. It has been shown that overexpression of CD146 predicts poor prognosis of solid tumor. Several reports by using transfectants or gene silencing technique have shown that CD146 is involved in cell adhesion and inflammatory cell migration. However, contribution of CD146 in tumor metastasis and antitumor immunity are still unknown. To investigate the effect of CD146 on tumor metastatic properties, we establish two subclones from DLD-1 (human colon adenocarcinoma cells) expressing CD146 or not. Both cell lines express epithelial tumor marker EpCAM and TROP2 equally, while CD146 (+) DLD-1 could only express CD44 variant v8–v10 and EphA2. Using metabolic assay, we found enhanced metabolism and decreased lactate production in CD146 (+) DLD-1. Consist with the morphological changes to mesenchymal features CD146 (+) DLD-1, the expression of E-cadherin and claudin-3 in tight junction were decreased in CD146 (+) DLD-1. In addition, CD146 (+) DLD-1 significantly increased the production of VEGF and the induction of various genes (slug, twist and zeb1) which are involved in epithelial to mesenchymal transition (EMT). Interestingly, the expression of immune checkpoint molecules including B7-H1, B7-DC (both PD-1 ligands), CD155 and IDO were up-regulated in CD146 (+) DLD-1 inducing the resistance of cytotoxic effect of activated lymphocytes. These results indicate that CD146 (+) DLD-1 strongly induces immune escape mechanism, thus demonstrating a new relationship between CD146 and EMT and anti-tumor immunity, which would be a new treatment and diagnostic target for immunotherapy.
Therapeutic Induction of Tertiary Lymphoid Structures in Melanoma using STING Agonists
Authors: Chelvanambi Manoj , Taylor Jennifer L , Fecek Ronald J , Storkus Walter J 
Published: January 2023

Abstract
Tertiary lymphoid structures (TLS) are non-encapsulated functional aggregates of T cells, B cells, dendritic cells (DC) and high endothelial venules (HEV) located in peripheral sites of chronic inflammation. TLS may serve as sites of local antigen presentation and immune priming that may protect against tumor progression. Homeostatic chemokines CCL19, CCL21 and CXCL13 produced by DCs and/or stromal cells are known to support secondary lymphoid organogenesis and also play key roles in TLS formation. Other DC-associated pro-inflammatory cytokines including lymphotoxin α, IL-36γ and type I interferons also appear to aid in organizing TLS. Hence, we hypothesize that appropriate therapeutic activation of DCs within the tumor microenvironment may serve to nucleate TLS in vivo, leading to slowed tumor progression. We found that activation of the cytosolic DNA sensor STING using ML-RR-S2-CDA, a murine and human STING agonist, leads to not only an expected increased production of type I interferons by CD11c+ DCs in vitro but also leads to increased transcript levels of TLS-associated cytokines/chemokines via activation of pIRF3 and pIRF7. In mice harboring B16.F10 melanomas, provision of STING agonists slows tumor growth in a host STING dependent manner. Further using immunofluorescence microscopy, we observed increased infiltration and clustering of CD3+ T cells and CD11c+ DCs and the induction of HEVs in treated tumors within tumor-associated TLS as early as 5 days post-treatment. Future studies will determine how TLS shape the local versus systemic protective T cell repertoire in treated animals.