bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical Screening
Authors: Schröder Matthias , Loos Simone , Naumann Svenja Kerstin , Bachran Christopher , Krötschel Marit , Umansky Viktor , Helming Laura , Swee Lee Kim 
Published: January 2023

Abstract
Tumors are infiltrated by cells of the immune system that interact through complex regulatory networks. Although tumor-specific CD8 T cells can be found in peripheral blood and tumor samples from cancer patients, their function is inhibited by immunosuppressive cells such as regulatory T cells, tumor-associated macrophages and myeloid-derived suppressor cells (MDSC). Recent clinical successes have demonstrated that alleviating immunosuppression and T cell exhaustion translates into long-term clinical benefits. Although tremendous progress has been achieved, tools that afford unbiased approaches and screenings to uncover new potential inhibitors or gene targets are lacking. In the present study, we describe a system based on immortalized progenitors that allows straightforward investigation of myeloid cells. We show that bone marrow progenitors immortalized through the transduction of NUP98-HOXB4 transgene can be differentiated into CD11b+Gr-1+ MDSC that express arginase-1 and PD-L1, produce reactive oxygen and nitrogen species and suppress T cell function in vitro. To uncover chemical probes that interfere with MDSC biology, we performed a chemical phenotypic screening and identified 3-deazaneplanocin A as novel modulator of MDSC functions. We characterized and compared the effect of 3-deazaneplanocin-A and all-trans retinoic acid, a well-known modulator of MDSC activity, on the expression of effector molecules and immunosuppressive functions of MDSC. Altogether, this proof-of-principle opens new possibilities for the identification of drugs targeting myeloid cells with immunosuppressive activities.
The Ron receptor tyrosine kinase plays a protective role in the development of CNS inflammation during health and disease states
Authors: Dey Adwitia , Allen Joselyn N , Fraser James W , Snyder Lindsay M , Cantorna Margherita T , Paulson Robert F , Hankey-Giblin Pamela 
Published: January 2023

Abstract
Neurodegeneration is characterized by severe central nervous system (CNS) inflammation. Macrophages are immune cells that closely regulate inflammation by taking on different activation states. The Ron receptor tyrosine kinase is expressed on tissue resident macrophages including microglia. An in vivo deletion of Ron (Ron KO) promotes inflammatory (M1) and limits reparative (M2) macrophage activation. Whether this response influences CNS tissue inflammation is not characterized. The objective of this study was to elucidate whether Ron expression plays a critical role in CNS inflammation in homeostasis and subsequently in disease models. During homeostasis with no interventions, Ron KO mice developed an inflammatory CNS niche with increased tissue expression of M1-associated markers TNFα, Cox-2 and iNOS when compared to WT-mice (P&lt;0.05). In a diet induced obesity(DIO) model of chronic inflammation, Ron KO mice exhibit exacerbated CNS inflammation with decreased expression of M2(Arg-1) and a robust increase in M1 markers compared to WT-mice following 27 weeks of high-fat-diet intervention(P&lt;0.05). Lastly, we evaluated the role of Ron in a disease model of Multiple Sclerosis, experimental autoimmune encephalitis (EAE). Ron KO-EAE mice exhibited higher disease severity from peak disease state and onward when compared to WT-EAE mice (P&lt;0.05). Ron KO mice had greater CNS expression of M1 markers relative to higher peripheral inflammation with increased IFNγ secretion from lymphoid organs during peak disease state(P&lt;0.05). Collectively these results illustrate how maintenance of Ron expression in the CNS could then be a potential therapeutic approach to treating various grades of inflammation underlying neurodegeneration.
BMP-2 Increases Articular Chondrocyte Maturation and Hypertrophy through a COX-2 Dependent Mechanism Associated with Inflammation.
Authors: Cottrell Jessica , Michaels Sarah 
Published: January 2023

Abstract
Rheumatoid arthritis is an autoimmune disease where the body perceives joint tissue as a foreign object and attacks it through the immune response. During this process the immune response destroys the native joint tissue and later replaces it with nonfunctional scar tissue. The joints and surrounding tissues continue to have uncontrolled chronic inflammation which produces perpetual pain, swelling, and tissue destruction. Cyclooxygenase-2 (COX-2) metabolizes arachidonic acid into eicosanoids which can regulate the inflammatory response and affect bone metabolism. When articular cartilage is damaged, bone morphogenetic protein-2 (BMP-2) is released from cells and can upregulate COX-2 expression. It is hypothesized that this BMP-2 induced COX-2 expression results in cartilage producing cells known as chondrocytes to advance to hypertrophy. In this study, articular chondrocytes harvested from wild type mice were treated with BMP-2 to determine if COX-2 expression could increase chondrocyte maturation and hypertrophy. Samples were collected at 0, 1, 2, 4, 7, and 14 days after treatment to analyze protein and gene expression. BMP-2 treated cells had statistically higher COX-2 mRNA and protein levels when compared to control cells. The expression of COX-2 on days 1 and 3 was followed by the expression of collagen 10a1 (a marker of chondrocyte hypertrophy) on days 7 and 10. These data suggest that BMP-2 directed COX-2 expression can affect chondrocyte maturation. In conclusion, this mechanism may contribute to the bone loss associated with chronic inflammation in diseases like rheumatoid arthritis.
Mer receptor tyrosine kinase signaling prevents TLR-mediated self-ligand sensing and aberrant selection in germinal centers
Authors: Schell Stephanie L , Soni Chetna , Fasnacht Melinda J , Cooper Timothy K , Rahman Ziaur S.M. 
Published: January 2023

Abstract
Mer receptor tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells and inducing immunoregulatory signaling cascades. We previously showed that Mer-deficient mice on a mixed B6 and 129 background (B6129F2.Mer−/−) have increased germinal center (GC) responses, T cell activation, and apoptotic cell accumulation within GCs. Whereas B6129F2.Mer−/− mice accumulate apoptotic cells in GCs, B6.Mer−/− mice do not accumulate apoptotic cells, resembling B6 mice. Therefore, we used these two models to mechanistically separate the effects of debris released from secondary necrotic cells as a result of apoptotic cell accumulation from those driven by the loss of immune regulation by Mer. Through the study of global and cell-type intrinsic TLR and MyD88 deficiency in B6129F2.Mer−/− mice, we found that GC B cell-intrinsic sensing of self-RNA, but not self-DNA, released from secondary necrotic cells drives self-antigen induced GC responses. While self-ligands drive the magnitude of GC response, the loss of Mer immunoregulatory signaling bolsters antigen presentation and APC-intrinsic TLR activation drives pro-inflammatory cytokine production. Further, the loss of Mer immunoregulatory signaling accelerates the onset of autoimmunity when B6.Mer−/− mice are crossed to autoimmune-prone B6.Sle1b mice (Sle1b.Mer−/−) due to the retention of autoreactive B cells in GCs. Collectively, Mer prevents the cell-intrinsic activation of GC B cells and APCs to regulate the magnitude of GC response and T cell activation, in addition to regulating GC selection events to prevent the development of autoimmunity.
The role of renal infiltrating CD11c+ cells in lupus nephritis
Authors: Liao Xiaofeng , Ren Jingjing , Reihl Alec , Pirapakaran Tharshikha , Reilly Christopher M , Luo Xin M 
Published: January 2023

Abstract
Lupus nephritis, a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), manifests as inflammatory infiltration of the kidney. Many types of leukocytes infiltrate the kidney during the progression of lupus nephritis, but the specific contributions of each infiltrating population are still unclear. In this study, we have found that CD11c+cells accumulate in nephritic kidneys of lupus-prone mice. These renal CD11c+ cells, forming clusters with infiltrating T cells, are proinflammatory and secreting cytokines that promote autoantibody production and Th17 response. They also produce chemokines that attract other leukocytes into the kidney. The surface phenotype (CD11b+CD115highCD135lowCX3CR1highFcgRIVhigh)suggests that they may be derived from mature monocytes and be activated by pathogenic immune complexes. Ex vivo co-culture experiments also suggest that they can maintain the survival of renal infiltrating T cells. To further demonstrate the role of these CD11c+ cells in vivo, we are currently depleting them by targeting CX3CR1, as they are a unique population of cells predominantly expressing a high level of CX3CR1. The results obtained from this study will be important for the understanding of lupus pathogenesis and identification of new therapeutic targets against lupus nephritis.
Complement protein C1q modulates lipoprotein metabolism in macrophage foam cells
Authors: Fraser Deborah A , Curiel Lizette , Budin Ryan , Pulanco Marc C 
Published: January 2023

Abstract
In the atherosclerotic lesion, macrophages ingest high levels of damaged, modified, low density lipoproteins (LDL), which accumulate in lipid droplets or defective lysosomes, generating macrophage foam cells which contribute to plaque instability and rupture. C1q, the recognition component of the classical complement cascade, opsonizes modified forms of LDL such as oxidized LDL, and promotes ingestion by macrophages. C1q has been shown to be protective in an atherosclerosis model in vivo and shown to improve macrophage foam cell survival in vitro. Autophagy is a catabolic pathway that plays a role in cellular survival and is an important process in many phagocytic cells, such as macrophages. We tested the hypothesis that C1q modulates macrophage lysosomal maturation during ingestion of oxLDL and increases autophagy in an atheroprotective manner to improve macrophage survival. Levels of autophagy initiation and elongation proteins, Beclin 1 and Atg5, are not modulated by C1q, but levels of autophagosome-associated proteins, LC3B-II and p62, were increased in immunoblot. Quantitative PCR revealed that the increase in p62 protein levels was not due to an increase in transcription. Immunofluorescence microscopy verified that the increase in LC3B and p62 by C1q resulted in an increase in autophagosome formation during oxLDL clearance. TEM verified the formation of double membrane vesicles. C1q also increased lysosomal acidification in macrophages during ingestion of oxLDL. These atheroprotective alterations to lipoprotein metabolism may be important in slowing disease progression, and provide insight into the protective role of C1q in early atherosclerosis.
Macrophages attenuate survival of intravenously administered human mesenchymal stromal cells by phagocytosis
Authors: Hasgur Suheyla , Desbourdes Laura M. , Guess Adam J. , Otsuru Satoru , Yu Minjun , Overholt Kathleen M. , Relation Theresa , Horwitz Edwin M. 
Published: January 2023

Abstract
Human mesenchymal stromal cells (MSCs) are increasing used in clinical trials for a diverse array of applications. Whether allogenic or autologous cells are used, unqualified efficacy has not been shown, suggesting the innate immune system may be impairing MSC activity. For example, MSCs inherently traffic to osteosarcoma (OS) rendering them potentially effective delivery vehicles of therapeutics; however, such strategies have not emerged, possibly due to inadequate tumor localization. We sought to enhance MSC trafficking to OS studying xenograft models of human osteosarcoma in nude and NOD-scid-IL2rγnull (NSG) mice. After IV infusion, firefly luciferase-expressing MSCs trafficked to the tumor in both models. Interestingly, we observed 3.5-fold greater bioluminescent signal per unit volume from the OS in NSG compared to nude mice, suggesting macrophages in nude mice may be clearing the MSCs. To test our hypothesis, we infused MSCs into tumor-bearing nude mice after clodronate-mediated macrophage depletion and in non-depleted controls. The macrophage-depleted nude mice showed 3.7-fold more MSCs tumor localization on day 11 compared with controls. To evaluate a role of macrophages, 4 hours after claret-labeled MSCs were infused into nude mice. Flow cytometric analysis of a single cell suspension of lung and spleen revealed a claret+ human CD90+ fraction, consistent with human MSCs, and a claret+ F4/80+ human CD90− fraction suggestive of macrophages that have phagocytosed MSCs. Fluorescence microscopy confirmed claret+ cells within macrophages. Since clodronate depletes splenic, but not pulmonary, macrophages the splenic macrophages likely have the greatest impact which can be mitigated by transient macrophage depletion.
Soy isoflavones and their metabolites modulate cytokine-induced NK cell function.
Authors: Mace Thomas A , King Samantha , Loftus Shannon , Farren Matthew R , McMichael Elizabeth , Young Gregory , Carson William E , Clinton Steven K , Lesinski Gregory B 
Published: January 2023

Abstract
Soybeans and foods derived from them are a rich source of phytochemicals that have been linked with beneficial effects on obesity, cancer, and inflammation. It is postulated that these immunomodulatory properties in particular, may contribute to their health promoting effects. However, the impact of soy bioactives on the functional properties of immune cell subsets is not fully understood. Upon ingestion, the profile of bioactive compounds derived from soy becomes increasingly complex. For example, soy isoflavones (genistein and daidzein) can be differentially metabolized by distinct populations of gut microbiota which promote their metabolism into compounds as O-desmethylangolensin (O-DMA) and equol. We hypothesized that soy phytochemicals alter natural killer (NK) cell signaling and function. Soy isoflavones and their metabolites did not alter the viability of healthy donor PBMC, even at high (25μM) concentrations. However, pre-treatment of PBMC with genistein (p=0.0009) and equol (p=0.002) decreased IL-12/18 induced IFN-γ production compared to controls. Genistein (p=0.002) and equol (p=0.0006) also decreased IL-12/18-induced IFN-γ production by human NK cells but did not alter cytotoxicity. Furthermore, in vivo studies revealed that C57BL/6 mice fed a soy-enriched diet produced less IFN-γ in plasma following administration of IL-12/IL-18 as compared to control-fed animals (p&lt;0.0001). This study provides insight into how dietary soy modulates NK cell functions and suggest the use of soy may interact with during chemopreventive or immune based therapies that act via NK cells.
Leukotriene (LT) B4 metabolites inhibit the LTB4-mediated responses of human neutrophils.
Authors: Archambault Anne-Sophie , Poirier Samuel , Lefebvre Julie S. , Larose Marie-Chantal , Turcotte Caroline , Martin Cyril , Provost Véronique , Boudreau Luc H. , Laviolette Michel , Surette Marc E. , Flamand Nicolas 
Published: January 2023

Abstract

CONTEXT
LTB4 is recognized as an excellent promoter of host defense. Indeed, it stimulates leukocyte functions mainly through the engagement of the BLT1 receptor. Of note, LTB4 induces phagocyte recruitment, the release of antimicrobial peptides, and potentiates the ingestion and the killing of pathogens. In humans, LTB4 has a short half-life and is rapidly metabolized into 12-oxo-LTB4 by monocytes/macrophages, or into 20-OH- and 20-COOH-LTB4 by neutrophils. Although LTB4 metabolites bind to the BLT1 receptor with high affinity, they poorly activate neutrophils.

HYPOTHESIS
We postulated that LTB4 metabolites might act as inhibitors of BLT1-mediated responses, therefore limiting the impact of LTB4 on human neutrophil functions and that inhibiting LTB4 degradation would enhance its effects on neutrophils.

RESULTS
20-OH-, 20-COOH-, and 12-oxo-LTB4 inhibited all LTB4-mediated responses of neutrophils we tested (migration, degranulation, leukotriene biosynthesis). 20-OH-LTB4 was as efficient as the BLT1 antagonist CP 105,696 and all LTB4 metabolites were more potent than the anti-inflammatory and pro-resolving lipids resolvin E1 and 5(S),6(R)-lipoxin A4. In contrast, the fMLP- and IL-8-mediated responses were not affected by the LTB4 metabolites. Inhibiting LTB4 degradation into 20-OH-LTB4 in neutrophils notably amplified the LTB4-induced kinase phosphorylation and diminished the chemokinetic effect of LTB4.

CONCLUSIONS
Our data indicate that LTB4 metabolites act as natural inhibitors of LTB4-mediated responses and that preventing LTB4 metabolism can modulate some functions of neutrophils. These results support the idea that preventing LTB4 degradation might enhance host defense by boosting innate immunity.
The severity of pulmonary congestion stemming from pseudomonal wound infection is influenced by IL-22 produced by ILC3 in burn mice after γ-irradiation
Authors: Ito Ichiaki , Kobayashi Makiko , Cox Robert A , Finnerty Celeste C , Herndon David N , Suzuki Fujio 
Published: January 2023

Abstract
Sepsis is severely developed after pseudomonal wound infection in mice with combined injuries (burn plus γ-irradiation). In the present study, we investigated the severity of pulmonary congestion caused by pseudomonal wound infection in combined injured mice. Combined injured mice were prepared after exposure to 15% TBSA burn and 5 Gy whole body γ-irradiation, as previously described. Mice exposed to burn injury or γ-irradiation alone served as controls. P. aeruginosa (10 CFU/mouse) was applied to burn wound area i.d. Bacterial growth in various organs of these mice was determined by colony counting. Also, the infection was pathologically examined by histochemical staining of tissue sections. Various cytokines in the alveolar lavage fluids of combined injured mice were measured by ELISA, and ILC3 in the lung tissue homogenates were analyzed by flow cytometry. In the results, P. aeruginosa grew violently in the lung of combined injured mice, as compared with both groups of control mice. The lung of combined injured mice histologically exhibited an alveolar thickening, abnormal structure, and pulmonary congestion. Although the number of ILC3 with IL-22 producing capacities was not increased in the lung of both groups of control mice, the large number of ILC3 was isolated from the lung of combined injured mice. Elevated levels of IL-22 were detected in the lung of combined injured mice. These results suggest that the severity of sepsis stemming from pseudomonal burn wound infection is influenced by ILC3 increased in the lung and their IL-22 products in combined injured mice.
Memory B cells are poised for robust antigen presentation by HLA-DO
Authors: Mellins Elizabeth D , Jiang Wei , Adler Lital , Macmillan Henriette 
Published: January 2023

Abstract
The B cell is a uniquely efficient APC due to expression of BCR for antigen uptake and delivery to MHCII-enriched compartments (MIIC), and key regulatory molecules, invariant chain (Ii), HLA-DM and HLA-DO. All professional APCs express Ii and DM, whereas expression of DO is limited to B cells, certain DCs and thymic medullary epithelia. DO levels change dramatically in B cells entering or exiting the germinal center (GC). To determine effects of DO on other components of the MHCII pathway, we delineated the intracellular distribution of DO, DM, MHCII, and class II-associated CLIP in T2 cells with or without DO or DM expression using structured illumination microscopy. The distribution at steady state shows a very restricted lysosomal destination (LAMP1+) for DO and DM, and dual destinations (surface and LAMP1+) for CLIP and MHCII. DO expression increased overall CLIP compared to DM+DO-cells, but almost doubled the percent of CLIP co-localized with LAMP1, establishing peptide exchange potential (PEP) within MIICs, but not any other compartments or the cell surface. PEP enhancement associated with DO expression is likely due to its regulation of DM activity, as neither the overall CLIP level nor the percent of DR in MIICs increased. We then evaluated the extent of PEP in distinct primary B cell populations isolated from human tonsils, including memory (CD38−/IgD−), naïve (CD38−/IgD+), and GC (CD38+/IgD−) B cells. The measurement shows PEPMemory (significantly) &gt; PEPNaïve &gt; PEPGC−, although the percent of CLIP among all class II peptides is naïve &gt; memory &gt;&gt; GC. These results argue that DO expression in memory B cells equips them for more efficient APC function upon re-encounter with antigen.
T-cell antigens in pediatric-onset multiple sclerosis: A unique window into early disease mechanisms
Authors: Mexhitaj Ina , Nyirenda Mukanthu , Arnold Douglas L , Marrie Ruth Ann , Banwell Brenda , Bar-Or Amit 
Published: January 2023

Abstract
Multiple sclerosis (MS) involves immune attacks on the CNS, leading to demyelination, axonal injury and increasing neurological dysfunction. Though T cells are implicated, the particular subsets and their antigenic targets remain unknown. In adult-onset MS, distinguishing immune responses that are consequences of, rather than cause of, injury, is difficult. In contrast, pediatric-onset MS offers an early window into disease mechanisms given the narrower gap from biological onset. We aim to identify and characterize disease-relevant antigen-specific effector T cell responses to traditional and novel antigenic targets involved early in the MS disease process.
Our group has implicated target antigens and T cell subsets in pediatric-onset MS, by following patients from time of an initial presentation with acquired demyelinating syndrome and comparing those confirmed to have MS with those who remain monophasic. A CSF proteomic study implicated novel axo-glial apparatus molecules as early injury targets, rather than traditional compact myelin antigens. A series of multiparameter flow-cytometry panels applied to pediatric peripheral blood mononuclear cells (PBMC) revealed that MS children harbor abnormally increased frequencies and pro-inflammatory cytokine responses of particular effector T cell subsets compared to controls.
We will develop assays, initially in fresh PBMC samples from adult MS and controls, then miniaturize the approach and validate it for use in the small numbers of available cryopreserved pediatric PBMC samples to quantify antigen-specific responses including proliferation and cytokine profiles of distinct disease-implicated T cell subsets to both traditionally and newly implicated antigens.