bluuebunny/crossref_metadata_2025_split huggingface dataset:
A myeloid population potentially corresponding to myeloid monocytic suppressor cells (MoMDSCs) is increased in the blood of Rheumatoid Arthritis patients and associated with osteoclastogenesis
Authors: Macaubas Claudia , Gaertner Fabian , Yeh Chia-Lin , Rajasekaran Narendiran , Ilstad-Minnihan Alexandra , Nakamura Mary C. , Mellins Elizabeth D. 
Published: January 2023

Abstract
The development of erosive arthritis and joint damage are common and severe complications of rheumatoid arthritis (RA). Erosions are caused by excessive activity of osteoclasts (OCs), the only known bone resorbing cells. OCs are myeloid lineage cells and can be generated in vitro from CD14+ circulating myeloid cells, using RANKL and M-CSF. To characterize circulating myeloid lineage cells in RA, we performed mass cytometry (CyTOF) analysis of blood from 11 RA patients and 10 age and gender-matched healthy controls. Using CITRUS analysis, we found a myeloid cell cluster that is significantly elevated in RA patients compared to healthy subjects. The phenotype of this cluster is CD11b+, CD14+, CD16−, HLA-DR-/lo, CCR2hi, RANKhi, and phosphorylated (p)STAT3hi. The surface phenotype of this cluster is associated with monocytic myeloid derived suppressor cells (MoMDSCs). Analysis by conventional flow of a separate group of 14 RA patients showed that frequency of these myeloid cells correlates with number of blood osteoclasts precursors (OCP) based on the in vitro assay. Baseline level of pSrc and pJNK in these cells also correlated with OCP numbers. Both of these molecules are involved in downstream signaling cascades involved in osteoclastogenesis and osteoclast survival. We also found that intermediate (CD14++CD16+) monocytes are elevated in RA, as previously described, but these cells did not show a positive correlation with OCP numbers. These results indicate that a group of myeloid cells, potentially corresponding to MoMDSCs, are elevated in the blood of RA patients. Their phenotype (high RANK, phosphorylated Src, phosphorylated JNK) and frequency indicate that they may be involved in osteoclastogenesis, as described in mouse models.
Identification of perturbations in macrophage polarization in active systemic lupus erythematosus.
Authors: Labonte Adam C. , Bachali Prathyusha , Catalina Michelle , Robl Robert , Geraci Nicholas S. , Lipsky Peter , Grammer Amrie 
Published: January 2023

Abstract
SLE is characterized by abnormalities in B cell and T cell function, but the role of disturbances in the polarization of macrophages (Mφ) into functional subpopulations is unclear. Gene expression profiles were analyzed to identify differentially expressed (DE) genes between healthy controls and patients with either inactive or active SLE. While hundreds of DE genes were identified in B and T cells of active SLE patients, there were no DE genes found in B or T cells from patients with inactive SLE compared to healthy controls. In contrast, large numbers of DE genes were found in myeloid cells (MC) from both active and inactive SLE patients, and many of these were Mφ polarization genes (M1: STAT1, SOCS3; M2: STAT3, STAT6, CD163). Weighted gene correlation network analysis (WGCNA) was used to identify modules of genes associated with clinical activity in SLE patients; among these were disease activity-correlated modules containing polarization signatures of predominantly M1-associated genes. No disease activity-correlated modules were enriched in M2-associated genes. Pathway and upstream regulator analysis of DE genes from both active and inactive SLE MC were cross-referenced with high-scoring hits from the drug discovery Library of Integrated Network-based Cellular Signatures (LINCS) to identify new strategies to treat both stages of SLE. In summary, altered MC gene expression is characteristic of both active and inactive SLE, and disease activity is associated with an alteration in the MC signature towards the M1 phenotype. These data suggest that while B and T cell hyperactivity are associated with active SLE pathology, myeloid cells potentially direct flare-ups and remission by switching between M1- and M2-like polarization states.
Functions of GATA-3 Expression in Regulatory T Cells During Type 1 and Type 2 Inflammation
Authors: Gurram Rama Krishna , Zhu Jinfang (Jeff) 
Published: January 2023

Abstract
The transcription factor GATA-3 is not only responsible for effector CD4 T cell differentiation, but also essential for the homeostasis and stability of regulatory T cells (Tregs). Previous study from our group has shown that mice with both T-bet and GATA-3 deletion in Tregs developed severe autoimmune disease correlated with Tregs switching from Tregs to Th17-like cells. However, mice with only GATA3 deletion in Tregs were normal at steady state. To determine the role of GATA-3 in Tregs during inflammation, we used Th1 and Th2 mouse models. Our results suggest that GATA-3-deficient Tregs lose their Treg phenotype during a Th1 inflammation induced by scurfy fetal liver transplantation. However, in an asthma model GATA-3 (fl/fl) Foxp3 YFP Cre mice displayed reduced asthma symptoms, without affecting Th2 cell accumulation, or IL-4 and IL-13 cytokine production in the lung. Therefore, we propose that the expression of GATA-3 in Tregs may prevent Tregs from converting into other Th subsets during type 1 inflammation. On the other hand, GATA-3 expression in Tregs may contribute to Th2 responses by switching Tregs into Th2 cells under type 2 environment.
Early burst of glycolysis in microglia regulates mitochondrial dysfunction in oligodendrocytes under neuro-inflammation
Authors: Giri Shailendra , Suhail Hamid , Singh Jaspreet , Kumar Ashok , Rattan Ramandeep 
Published: January 2023

Abstract
Brain resident microglia plays a pathological role in the loss of oligodendrocyte’s function under neuroinflammation. The precise signaling mechanism by which microglial driven factor attenuates the myelin gene expression under such condition is poorly defined. Here we used bioenergetic approach to understand the microglia-oligodendrocyte crosstalk. We found that mixed glial cells under inflammatory stimulation using lipopolysaccharide plus interferon gamma (LI) had significantly enhanced glycolysis with drastic attenuation of mitochondrial respiration and myelin gene expression. Dissecting the mixed glial culture into pure microglia, astrocyte and oligodendrocytes (OLs) revealed that primary microglia was the main source of higher glycolysis, inflammatory cytokines, and nitric oxide (NO). An early burst of glycolysis in microglia in response to LI treatment caused the production of inflammatory cytokines and NO, which is mediated by PDK1-Akt signaling. Culturing of OLs with LI-conditioned microglial media (mCM) resulted in complete failure of mitochondrial respiration in OLsalong with decreased expression of myelin genes. We identified that nitric oxide produced by microglia is the key player in the loss of mitochondrial respiration in OLs and targeting either glycolysis, PDK1 or Akt in microglia resulted in significant recovery of mitochondrial function and myelin genes expression in OLs. In summary, we identified a potential therapeutic signaling cascade in microglia; an early burst of glycolysis mediated by PDK1 and Akt, responsible for hyper-production of NO, ensuing in the failure of mitochondrial respiration in oligodendrocytes, and leading in reduction of myelin genes expression.
Modulation of TLR2/1 by PAM3CSK4 to induce generation of immunosuppressive macrophages as a therapeutic approach for SLE
Authors: Horuluoglu Begum Han , Bayik Defne , Goguet Emilie , Tross Debra , Blanco Luz P. , Kaplan Mariana J. , Klinman Dennis M. 
Published: January 2023

Abstract
Systematic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the overproduction of autoantibodies and the chronic inflammation of multiple organs. Early studies suggested that T and/or B cell abnormalities were critical to disease pathogenesis in lupus patients. More recent work shows that abnormalities in the innate immunity play a contributory if not central role. In that context, we find that SLE patients have significantly more CD14lowCD16+ monocytes compared to healthy controls.CD14lowCD16+ monocytes are a subset known as non-classical monocytes and display inflammatory characteristics upon activation. The frequency of inflammatory macrophages correlates with disease severity and is associated with reduced clearance of apoptotic cells and the overproduction of inflammatory cytokines.
We previously found that the TLR2/1 agonist PAM3CSK4 (PAM3) can inhibit the generation of M1- while promoting the generation of immunosuppressive M2-like macrophages. This work examines whether PAM3 can shift the M1:M2 macrophage ratio to restore balance in lupus patients. Even though phenotypically, PAM3 did not seem to induce as many as CD163+ (a functional marker of M2) macrophages like M-CSF did, there was no significant difference in the endocytosis ability of the CD163+ macrophages induced by PAM3 compared M-CSF induced ones. The in vivo activity of PAM3 was investigated in the NZB/W murine model of lupus. Preliminary results indicate that, PAM3 injection increases the survival and decreases proteinuria in mice sera. These findings suggest that PAM3 may promote the polarization of SLE monocytes into immunosuppressive macrophages and thus could represent a novel approach to the therapy of this autoimmune disease.
SLAMF9 promotes inflammation and resistance to Salmonella infection
Authors: Wilson Timothy James , Clare Simon , Lyons Paul , Dougan Gordon , Smith Ken G. C. 
Published: January 2023

Abstract
SLAMF9 is an uncharacterized member of the CD2/SLAM family of cell surface receptors. Unlike other members of the SLAM-family, it contains no phosphorylated tyrosines or recognizable signaling motifs, and neither homotypic nor heterotypic interactions between SLAMF9 and other members of the SLAM family have yet been observed. Through generation of Slamf9−/− mice and novel antibody reagents, we have determined that SLAMF9 is expressed on plasmacytoid dendritic cells, B1 cells, and select populations of tissue-resident mononuclear phagocytes. RNA interference experiments in human THP-1 monocytes indicate that SLAMF9 is important in the production of pro-inflammatory cytokines following stimulation with TLR agonists, and infection of Slamf9−/− mice demonstrate the importance of SLAMF9 in clearance of systemic Salmonella Typhimurium infection.
Cerebrospinal fluid neopterin and CXCL13 are suitable biomarkers for staging and detection of treatment failure in a non-human primate model of human African trypanosomiasis
Authors: Maranga Dawn , Ngotho Maina , Mwadime Victor , Olouch George , Adino Thomas , Kagira John , Waema Maxwel , Bieler Sylvain , Ndung’u Joseph 
Published: January 2023

Abstract

Background
Follow-up of treated human African trypanosomiasis (HAT) patients has been a routine practice for confirming cure and early detection of treatment failure.

Objective
The aim of this study was to verify suitability of neopterin and CXCL13 as disease stage biomarkers and monitors of treatment efficacy in a vervet monkey model of HAT.

Methods
Six monkeys were infected with Trypanosoma brucei. Late stage disease was induced by sub-curative treatment with diminazene aceturate (DA) from 28 days post-infection (dpi). Upon relapse, the animals were treated curatively with melarsoprol (Mel B) from 82 dpi. Blood and cerebrospinal fluid (CSF) samples were collected weekly and assessed for parasitosis, as well as tested for neopterin and CXCL13 by ELISA, for a period of 39 weeks.

Results
Neopterin concentrations in serum increased rapidly after infection in early disease (stage 1), peaking at 14 dpi. Levels then dropped rapidly to pre-infection levels by 35 dpi. In contrast, there was a marginal increase in CSF neopterin during early infection, with a minor peak at 21 dpi. Serum CXCL13 increased rapidly from 7 dpi, peaking at 28 dpi. Levels dropped upon sub-curative treatment with DA. CXCL13 concentrations in CSF also increased gradually in early stage disease and continued to rise after sub-curative treatment with DA. Curative treatment with Mel B resulted in its gradual decline, reaching pre-infection levels 105 days later.

Conclusions
CSF neopterin and CXCL13 peak levels coinciding with time of relapses demonstrates the potential of these biomarkers in staging and detecting treatment failure. Moreover, the rapid fall in CSF neopterin after curative treatment confirms its great potential for use in development of a test of cure.
Peptide-Specific Engagement of Cerebrovascular Endothelial Cells Promotes Dysfunctional Calcium Signaling During Experimental Cerebral Malaria
Authors: Manglani Monica , Silva Alexander , McGavern Dorian 
Published: January 2023

Abstract
Cerebral malaria is a potentially fatal complication associated with Plasmodium falciparum infection. Disease pathology includes blood brain barrier (BBB) breakdown, microvascular hemorrhage, edema and brainstem herniation. Studies in rodents (referred to as experimental cerebral malaria) have revealed that parasite-specific CD8+ T cells induce this pathology via engagement of cerebrovascular endothelial cells (ECs). In this study, we sought novel insights into the mechanisms underlying alterations in BBB structure and function during the development of ECM. We developed a novel transgenic reporter system that allowed us to simultaneously monitor calcium signaling in cerebrovascular ECs and parasite-specific CD8+ T cells. We then used intravital two-photon microscopy (TPM) to monitor BBB dynamics in real-time at the peak of disease. Within venous networks, we observed a significant increase in the magnitude and propagation of EC calcium signaling. Calcium wave propagation along lengthy stretches of cerebrovascular endothelium was associated with regions of parasite-specific CD8+ T cell engagement (both stable and dynamic). Recognition of cognate peptide-MHC on luminal and abluminal EC surfaces resulted in calcium fluxes within parasite-specific CD8+ T cells, which was followed temporally by calcium wave propagation in the associated vasculature. Importantly, this pathophysiological response was completely eliminated by depletion of T cells. We postulate that T cell-mediated induction of calcium waves along cerebral blood vessels promotes noncytopathic disruption of the BBB. Therapeutic manipulation of this activity might help restore BBB homeostasis and prevent neurological complications during ECM.
Voluntary physical exercise decreases MDSC (myeloid derived suppressor cell) populations in the spleen and circulation in a rat model of mammary adenocarcinoma
Authors: Hirsch Aspen L. , Brenner Cassandra L. , Costa Alex B. , Haughian James M. , Pullen Nicholas A. , Hayward Reid 
Published: January 2023

Abstract
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid progenitor cells that suppress T cells and other potentially anti-cancer immune cells. MDSC presence in cancer patients can diminish immunotherapy response and worsen treatment outcomes. Here we examine a low-risk, low-cost approach to MDSC modulation by examining the impact of voluntary wheel-running exercise on MDSC populations in a Fisher-344 rat, MATBIII mammary adenocarcinoma model. Rat MDSCs in blood, spleen, bone marrow, and tumor tissue were identified by dual expression of surface markers His48 and CD11b and confirmed to be immunosuppressive upon sorting and interrogation in an in-vitro T cell suppression assay. We find that the percentage of MDSCs (as a proportion of total cells) is reduced in whole spleen isolates (2.55% vs. 19.68%, P≤0.005) and in the circulating white blood cell fraction (1.33% vs. 23.21%, P≤0.05) of exercised versus sedentary animals. In contrast, we find no difference between the proportion of MDSCs as a population of total cells in bone marrow (23.57% vs. 25.52%, P≥0.05) or tumor tissue (11.68% vs. 7.10%, P≥0.05). We conclude that exercise decreases splenic and circulating MDSC populations in tumor bearing animals. Further studies are necessary to establish the molecular mechanisms of this suppression to leverage potential interactions between exercise and MDSC-directed immune therapies.
TFEB regulates tumor-associated macrophages in breast cancer through autophagy-dependent and independent pathways
Authors: Fan Daping , Hodge Johnie , Fang Liang 
Published: January 2023

Abstract
Tumor-associated macrophages (TAMs) play a key role in tumor development in breast cancer, as they are educated in the tumor microenvironment to assist tumor growth and metastasis. We identified an important role of TFEB, a master regulator of autophagy and lysosome biogenesis, in phenotypic regulation of TAMs. In human breast cancer and mouse orthotopic breast tumors, TFEB expression and activation are down-regulated in TAMs. Previously we showed that TFEB inhibits macrophage M2 polarization through a SOCS3-STAT3 pathway. Our new microarray analysis and qPCR confirmation demonstrate that TFEB overexpression in macrophages not only significantly suppresses the induction of typical M2 genes Arg1 and IL-10 by breast cancer cell conditioned medium, but also significantly inhibits the induction of inflammatory response axis NLRP3/IL1β/IL6 and PGE2 generation axis HIF-1α/MIF/cPLA2/COX2. These two axes are known to be tumor-promoting. Further analyses indicate that TFEB regulates these two axes through both autophagy-dependent and autophagy-independent pathways. Animal studies show that macrophage-specific TFEB overexpression inhibits, while macrophage-specific TFEB deficiency enhances breast tumor growth and metastasis. Furthermore, activation of TFEB using two natural compounds halts breast cancer development in mice. Taken together, our data suggest that activation of macrophage TFEB could be developed as a therapeutic strategy against breast cancer.
Development of melittin-based anti-cancer drug for targeting tumor-associated macrophages
Authors: Lee Chanju , Jeong Hyunju , Bae Hyunsu 
Published: January 2023

Abstract
Tumor-associated macrophages (TAMs) are the major component of tumor infiltrating immune cells. Macrophages are broadly categorized as M1 or M2 types and TAMs have been known to express M2-like phenotype. TAMs promote tumor progression and contribute to resistant to chemotherapies. Therefore, M2-like TAMs are potential targets for the treatment of cancers. In this study, we targeted M2-like TAMs using a hybrid peptide MEL-dKLA composed of melittin (MEL) peptide, which binds preferentially to M2-like TAMs and d-KLAKLAKKLAKLAK (dKLA) peptide, which induces apoptotic cell death after cell membrane penetration. We showed that the MEL-dKLA induced selective cell death of M2 macrophages by disrupting mitochondrial membrane in vitro while MEL did not show the correlation with mitochondrial apoptosis. We also showed that MEL-dKLA selectively targeted the M2-like TAMs without affecting other leukocytes such as T cells and dendritic cells in vivo. It resulted in the inhibition of tumor growth rate and tumor weight, and angiogenesis in vivo. Importantly, although both MEL and MEL-dKLA reduced the CD206+ M2-like TAMs in the tumor, only MEL-dKLA induced the apoptosis of CD206+ M2-like TAMs whereas the MEL did not show the cell death. Taken together, our study describes MEL-dKLA can be used as the promising therapeutic agent for targeting M2-like TAMs.
Cross Reactivity of CD8+ T Cell Neo-epitopes to Bifidobacterium Boosts the Tumor Specific Population
Authors: Bessell Catherine Ami , Isser Ariel , Havel Jonathan , Chan Timothy , Schneck Jonathan P. 
Published: January 2023

Abstract
The interplay between the microbiome and the anti-tumor T cell specific response is a rising field in cancer immunotherapy. The effect of antigen homology between commensal bacteria and neo-antigen specific responses in tumors has, in concept, a high degree of targeted application. The neo-antigen response is a tumor specific antigen rising from mutation in the tumor cells has been associated with an increased anti-tumor ability with immunotherapy. Using a model of neo-antigen specificity with Kb-SIY in B16-SIY melanoma and commensal bacteria Bifidobacterium we identified a model of antigen mimicry for neo-antigen. Commensal bacteria antigen “Kb-SVY” is not inhibited from binding into the MHC molecule and leads to stable peptide MHC interactions. T cell populations for Kb-SIY and Kb-SVY show cross-reactivity for homologous antigens. And the impact of Bifidobacterium on the developing response show an in vivo priming to create a robust commensal bacteria response that contributes to the anti-tumor activity.
Targeting EZH2 Selectively Alters Intratumoral Regulatory T Cells to Enhance Cancer Immunity
Authors: DuPage Michel , Wang David , Quiros Jason , Mahuron Kelly , Pai Chien-Chun , Ranzani Valeria , Young Arabella , Silveria Stephanie , Harwin Tory , Abnousian Arbi , Pagani Massimiliano , Rosenblum Michael , Van Gool Frederic , Fong Lawrence , Bluestone Jeffrey A. 
Published: January 2023

Abstract
Immunosuppressive regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Targeting Tregs may be a powerful means to unleash more potent immune responses against cancer, but targeting these cells is challenging because their generalized inactivation may incite severe autoimmune toxicities. To selectively target Tregs in tumors, we investigated the role of the H3K27 methyltransferase EZH2 in Tregs and determined that its enhanced activity at tumor sites in mice and humans leads to more robust and stable Tregs. We demonstrate that blocking EZH2 activity, both pharmacologically and genetically, selectively reprograms the function of tumor-infiltrating Tregs without systemically altering Treg function. Genetic disruption of EZH2 in tumor-resident Tregs led to their acquisition of pro-inflammatory functions that remodeled the tumor microenvironment and enhanced the recruitment and function of effector T cells, leading to the complete elimination of tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a novel strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
Generation of murine tumor cell lines to assess in vivo anti-tumor immune responses to melanoma.
Authors: Hope Jennifer L. , Henriquez Monique L. , Tinoco Roberto , Bradley Linda M. 
Published: January 2023

Abstract
Mouse models of cancer remain the preferred means to assess the efficacy of anti-cancer therapies, and several models have been used to address the effect of cancer drugs or in the discovery of biomarkers. The Yale University Mutant melanoma lines, YUMM1.5 and YUMMER1.7 murine tumor models were developed from the BrafV600E/Pten/−/−Cdkn2a−/− engineered mouse model to more closely reflect poorly immunogenic and highly mutated melanomas, respectively, that are driven by human disease-relevant mutations; however, the dominant T cell-recognized epitopes specific for these tumors remains unknown. We therefore sought to engineer OVA-expressing versions of the YUMM1.5 and YUMMER1.7 tumor lines, hereafter referred to as YUMM1.5-OVA and YUMMER1.7-OVA. Using stable transfection to insert a plasmid expressing full-length secretory ovalbumin, we have generated polyclonal and monoclonal cell lines that generate an in vivo OVA-specific response as validated by MHC class I tetramer staining and cytokine production following OVA peptide stimulation. Together, these two new models for melanoma tumors will allow us to assess intrinsic and extrinsic mechanisms regulating the generation of effective and recovery of exhausted T cell responses to melanoma in vivo.