bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational approach to identifying universal macrophage biomarker
Authors: Dang Dharanidhar , Prince Lawrence S , Sahoo Debashis 
Published: January 2023

Abstract
Macrophages are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface. Understanding gene expression dynamics in macrophages are crucial for studying human diseases. Recent advances in high-throughput technologies have enabled the collection of immense amounts of biological data. A reliable marker of macrophage is essential to study their function. Traditional approaches use a number of markers that may have tissue specific expression patterns. To identify universal biomarker of macrophage, we used a previously published computational approach called BECC (Boolean Equivalent Correlated Clusters) that was originally used to identify universal cell cycle genes. We performed BECC analysis on a seed gene CD14, a known macrophage marker. FCER1G and TYROBP were among the top candidates which were validated as strong candidates for universal biomarkers for macrophages in human and mouse tissues. To our knowledge, such a finding is first of its kind.
Selective killing of proinflammatory human M1 macrophages by SMAC mimetics and anti-inflammatory M2 macrophages by SMAC mimetics and caspase inhibitors
Authors: Kumar Ashok , Ali Hamza 
Published: January 2023

Abstract
The inflammatory and anti-inflammatory macrophages have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis and leprosy. Targeting macrophage function and activation may represent a potential target to treat these diseases. Herein, we investigated the effect of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of human pro- and anti-inflammatory macrophage subsets. We have shown previously, that human monocytes are susceptible to the cytotoxic effects of SMs, however, differentiated macrophages (M0) are resistant. Whether human macrophage subsets are also resistant to the cytotoxic effects of SM remains unknown. We show that differentiation of M0 macrophages towards M1 state rendered them highly susceptible to SM-induced cell death, whereas M2a, M2b and M2c subsets were resistant, with M2c being the most resistant. SM-induced cell death in M1 macrophages was mediated by apoptosis as well as necroptosis, and activated both extrinsic and intrinsic pathways of apoptosis. The susceptibility of M1 macrophages to SM-induced cell death was attributed to the IFNg-mediated polarization as JAK inhibitor reversed their susceptibility. In contrast, M2c and M0 macrophages experienced cell death through necroptosis pathway following simultaneous blockage of the IAPs pathways by SM and the caspase pathways by the pan-caspase inhibitors. Overall, the results suggest that survival of human macrophages is critically linked to the activation of the IAPs pathways. Moreover, agents blocking the cellular IAP1/2 and/or caspases can be exploited therapeutically to address inflammation-related diseases.
Characterization of renal macrophage (RM) fate, dynamics, and niches: embryonic RMs are more sensitive to immune challenges than bone marrow-derived RMs
Authors: Qin Xuebin , Liu Fengming , Qin Zhongnan , Rappaport Jay 
Published: January 2023

Abstract
Renal macrophages (RMs) participate in tissue homeostasis, inflammation, and repair. RMs consist of embryo-derived (EMRMs) and bone marrow-derived RMs (BMRMs), but the fate, dynamics, replenishment, functions, and metabolic states of the two RM populations remain unclear. Answering these questions will advance our understanding of the pathophysiological functions of tissue macrophages, in general, and RMs, in particular. To begin to address these important questions, we systematically investigated and functionally characterized RMs at different ages by conditionally labeling and ablating RM populations in several lines of transgenic mice. Here, we demonstrate: 1) RMs expand and mature in parallel with renal growth after birth; 2) RMs are mainly derived from fetal liver monocytes before birth, and self-maintain through adulthood with an approximately 40% contribution from peripheral monocytes; 3) After the RMs niche is emptied, peripheral monocytes rapidly differentiate into BMRMs, which preserve longevity; 4) The CX3CR1/CX3CL1 axis provides RMs niche signaling essential for the maintenance and regeneration of both EMRMs and BMRMs; 5) EMRMs have a higher capacity for scavenging immune complexes and are more sensitive to immune challenge than BMRMs; and 6) Differences in the glycolytic capacities of EMRMs and BMRMs correlate with distinct intrinsic functions and the response to immune challenge of the two RM populations.
Immune profiles in experimental two-Kidney-one-cuff (2K-1C) model of renovascular hypertension that predicts reversible versus irreversible renal injury
Authors: Osman Mazen , De Lorenzo Silvana , Johnson Ruth , Grande Joseph 
Published: January 2023

Abstract
Renal artery stenosis is common in the elderly population; biomarkers that predict response to restoration of blood flow have not been previously established.

Methods
We have previously shown in murine model that cuff removal 7 days (7D Cuff-off) after initial placement on the renal artery results in reversible injury whereas cuff removal 14 days (14D Cuff-off) after placement results in irreversible renal injury, when assessed at 28 days after initial surgery. Positive and negative controls consisted of cuff placement for 28 days (28D) and sham surgeries respectively. We performed RNASeq on whole renal cortex to identify innate immune pathways that correlate with reversible versus irreversible injury. Data were normalized to appropriate sham controls in all the groups. Induction of greater than log2 ratio &gt; 2 and p &lt; 0.00001 were considered significant (following adjustment for multiple comparisons).

Results
As assessed by RNASeq, progression of renal disease (14D Cuff-off & 28D mice) was associated with persistent upregulation of genes associated with T cell signaling and macrophage polarization compared to reversible injury (7D Cuff off). Upregulated genes included but not limited to: CCL5, CCR5, CCL2, CXCL1, CXCL9, CXCL10, CXCR3, TLR2, KLF6, CD74, CD4, CD14, CD44, CD83, CD84, IL1R1, IL1B, SPP1, AIF1, SLC7A2, TRAF1, S100A4, SLC9A9, CRIP1, CLEC7A, CLEC10A, EGR2, MGL2, SOCS2, CTLA2B, and FCGR1.

Conclusion
We have identified genes associated with T cell and macrophage activation that were down regulated in the 7D Cuff-off versus 14D Cuff-off and 28D mice; future studies in isolated T cells and macrophages will determine whether these genes represents biomarker(s) of renal disease progression in 2K-1C renovascular hypertension.
PRMT5 has roles in thymic/peripheral T cell development and EAE
Authors: Sengupta Shouvonik , Webb Lindsay M , NarvaezMiranda Janiret , Amici Stephanie A , Edell Claudia , Guerau-de-Arellano Mireia 
Published: January 2023

Abstract
Protein Arginine Methyltransferase (PRMT) 5 is a type-II methyltransferase involved in oncogenesis, embryonic and hematopoietic development. However, the role of PRMT5 T-cell biology is only now coming into focus. To evaluate PRMT5’s functions in T-cells, we have developed a conditional knock-out (KO) model that allow for a deletion of PRMT5 during thymic development, by knocking-out PRMT5 in all peripheral T cells (T-PRMT5D/D). Using this model that deletes both protein-coding isoforms of Prmt5, we investigated the role of the PRMT5 gene during T-cell development, proliferation and experimental autoimmune encephalomyelitis (EAE). We saw reduced numbers of CD4+ T-cells, Tregs and iNK T-cells in the thymus. CD4+, Treg and iNK T-cell number defects were seen in the peripheral lymphoid organs such as spleen and lymph nodes. Peripheral analyses also showed reduced CD8+ T-cells, naive, effector and central memory CD4+ T-cells. We also induced PRMT5 deletion specifically in peripheral CD4+ T cells (iCD4-PRMT5D/D). We utilize this model to induce PRMT5 deletion specifically in peripheral CD4+ T cells while ensuring that the mice develop normal numbers of peripheral T cells. Using this model, we showed that EAE was completely abolished in the mice. Total CNS infiltrating T-cell numbers were substantially reduced, and significant losses were observed in the Th1 and Th17 cytokine production from these cells. These data substantively demonstrate a driver role for PRMT5 in thymic CD4 Th cell development, peripheral CD4+, iNKT and CD8+ T-cell maintenance and Th cell-mediated EAE autoimmunity.
Enhanced N-glycan branching on CD8 T cells exacerbates autoimmune diabetes in non-obese diabetic mice
Authors: Chien MingWei , Sytwu HueyKang 
Published: January 2023

Abstract
β1,6N-acetylglucosaminyltransferase V (Mgat5), is responsible for tetra-antennary N-glycans in the biosynthesis of glycoprotein and the resultant N-glycan branching serves as a backbone for additional glycosylation such as poly-N-aceyllactosamine (poly-LacNAc) structure. The N-glycan branching is involved in the pathological conditions such as malignancies, but the modulatory roles of N-glycan branching on T cells in autoimmune diabetes is not completely understood. Here, we report that the levels of N-glycan branching on T cells is positively correlated with the diabetogenesis in NOD mice. Since the levels of N-glycan branching is regulated during T-cell development and highly increases in pathogenic lymphocytes in pancreas, we generated established T cell-specific Mgat5 transgenic and mutant NOD mice. Interestingly, our results demonstrated that the diabetic incidence in Mgat5 transgenic mice was significantly higher and that of Mgat5 mutant mice markedly attenuated compared to control NOD mice. In adoptive transfer experiments, NOD/SCID mice that received control CD4 T cells plus transgenic CD8 T cells developed diabetes more rapidly than the mice received control or transgenic CD4 T cells plus control CD8 T cells, suggesting that the diabetogenicity in Mgat5 transgenic mice is a CD8 T cell–autonomous manner. Moreover, we generated Mgat5/NY8.3 doubly transgenic NOD mice expressing highly pathogenic MHC class-I-restricted 8.3 T cell receptor, and observed that these mice have higher diabetic incidence than wild-type NY8.3 transgenic NOD mice. Taken together, enhanced N-glycan branching on CD8 T cells exacerbates the development of diabetes in NOD mice.
The C3-like molecule CD109 controls Th1 versus Th17 induction in CD4+ T cells
Authors: Merle Nicolas S , Kolev Martin , Rahman Jubayer , West Erin , Yan Bingyu , Kazemian Majid , Afzali Behdad , Kemper Claudia 
Published: January 2023

Abstract
Recent work defined an unexpected and critical role for intracellular/autocrine active complement in human Th1 biology. Specifically, autocrine stimulation of CD46 via TCR-induced C3b generation is needed for IFN-γ production by human CD4+T cells. Analysis of the CD46-driven gene signature in Th1 cells revealed CD109, a C3-like surface protein known to regulate TGF-β signaling, as a direct target of CD46. We confirmed that T cells from patients with CD46 deficiency, which suffer from recurrent infection due to reduced Th1 responses, and from healthy donors knocked-out for CD46 via CRISPR-Cas9 technology failed to upregulate CD109. CD109 is expressed on keratinocytes, endothelial and stem cells and overexpression is connected with cancer but its function on T cells remains unexplored.
In vitro activation of mouse Cd109−/− CD4+ T-cells showed a strong increase of Th1- and Th17-related cytokines compare to their WT counterpart. In line with this observation, Cd109−/− mouse CD4+ T cells showed an increase in IL-17A+ and IFN-γ+/IL-17A+ T cell numbers in vivo and caused significantly more weight loss and disease pathology in a T cell-transfer colitis model. Although CD109 is known to regulate TGF-β signaling, our RNA-sequencing analysis of activated Cd109−/− mouse T cells revealed that this molecule is restraining Th17 induction rather via impact on cell cycle and apoptosis related pathways, which we are investigating now.
Together, these data suggest that the complement-related protein CD109 serves as an important and novel molecular switch on CD4+ T-cells, where it regulates the balance between Th1 and Th17-induction pathways.
Pregnancy drives TCR-dependent and -independent changes in maternal T cells
Authors: Krupp Katharine , Xu Rong , Porrett Paige 
Published: January 2023

Abstract
Pregnancy is a significant immunological event, which has been shown to induce changes in maternal T cells. Studies examining maternal T cell responses in pregnancy have largely been conducted using mice that express transgenic “surrogate” fetal antigens, and have focused mainly on divided alloreactive T cells. Yet, maternal T cells may exhibit a broader range of responses during pregnancy some of which may not rely upon TCR signaling or cellular proliferation. To investigate the full spectrum of endogenous maternal T cell responses in natural pregnancy, we used the Nur77 mouse model, which allows for a graded assessment of TCR signaling using a GFP reporter. Splenocytes from female CD45.2 Nur77 mice were labeled with CellTrace Violet (CTV) to detect cellular division and transferred into female CD45.1 congenic mice. These host females were then mated with either syngeneic CD45.1 or allogeneic Balb/c males or left naive non-mated controls. Splenocytes were collected on either embryonic day 10 or 18 (E10 or E18) and analyzed using flow cytometry.
t-SNE analysis revealed few phenotypic differences between the experimental groups at E10 with significantly increased separation by E18, which was most evident in the CD4 compartment. Interestingly, this separation was driven primarily by changes in the expression of selectins (i.e. downregulation of CD62L) and cytokine receptors (i.e. increased expression of CD25) as opposed to changes in TCR signaling (GFP) or cellular division (CTV). Accordingly, we conclude that maternal T cell responses in pregnancy are significantly shaped by non-antigen driven signals. The functional impact of these non-antigen driven changes in cellular phenotype are unknown and currently under investigation.
Surfactant protein receptor SP-R210 isoforms play a role in regulating macrophage immune response in conjunction with epigenetic changes during Influenza A infection
Authors: Yau Eric , Song Chunhua , Kawasawa Yuka Imamura , Chroneos Zissis C 
Published: January 2023

Abstract
Alveolar macrophages (AMs) and surfactant proteins are critical for host defense and regulation of immune responses to airborne pathogens like influenza A virus (IAV). Previous findings showed that the surfactant protein A receptor SP-R210 regulates macrophage responses to LPS and phagocytic flux. Our goal is to understand how the long (L) and short (S) isoforms of SP-R210 alter macrophage responses to respiratory pathogens. Here we investigated how altering expression of the L isoform changes macrophage epigenetic landscape during IAV infection. Chromatin immunoprecipitation and sequencing were used to identify alterations in H3K4me3, H3K9me3, and H3K27me3 histone methylation and PU.1 transcription factor binding in L knockdown (KD) cells at baseline and after IAV infection. The UCSC genome browser was used to identify spatial relations of enriched binding regions, revealing reduced PU.1 binding at genes associated with macrophage differentiation and signaling between innate and adaptive immune cells, such as interleukin 18 (IL-18) and colony-stimulating factor receptors (CSF1R, CSF2RB) in KD cells. These changes were mirrored with decreased H3K4me3 marks in KD macrophages. Further analysis with ChIPseeker revealed enrichment in Toll-like receptor and interferon signaling pathways in KDmacrophages. IAV infection upregulated PU.1 binding to genes associated with IL-3, IL-5 and TLR4 signaling pathways among others. RNA sequencing confirmed increased TLR4 and TLR6 and decreased IL-18 transcripts in KDmacrophages. These findings support the idea that the L isoform of SP-R210 regulates chromatin architecture and accessibility of transcription factors at genes with roles in macrophage differentiation and activation.
Cardiolipin dynamics regulate proinflammatory cytokine production in methicillin-resistant Staphylococcus aureus--infected macrophages
Authors: Reynolds Mack B , Abuaita Basel H , O’Riordan Mary X 
Published: January 2023

Abstract
During the immune response, mitochondria serve as a hub for innate immune signaling molecules, such as mitochondrial antiviral signaling protein (MAVS) and Nod Like Receptor Family Pyrin Domain Containing 3 (NLRP3). Cardiolipin, a class of phospholipids found primarily in the inner mitochondrial membrane (IMM), regulates mitochondrial function and cellular stress. In lipopolysaccharide (LPS)-stimulated macrophages, CL translocates from the IMM to the outer mitochondrial membrane (OMM) and recruits NLRP3 to promote inflammasome activation. However, the role of CL in macrophage antibacterial responses remains ill defined. Here, we have made CL-deficient RAW264.7 (RAW) cells by stably knocking down Cardiolipin Synthase (Crls1). Upon infection with methicillin-resistant Staphylococcus aureus (MRSA), Crls1 KD RAW cells showed markedly decreased expression and production of cytokines IL-6, IL-1β, and IFN-β compared to control cells, while TNF-α levels remained similar. For IL-6 and IFN-β, transcript and protein levels in Crls1 KD RAW cells were comparable to unstimulated controls. Surprisingly, these cells showed normal MRSA killing and NF-kB p65 nuclear translocation. These findings suggest a novel role for CL in transcript-level regulation of cytokines during infection. To further investigate CL-dependent innate immune functions, we will use RAW cells expressing a GFP-tagged CL-binding protein, Stomatin-like Protein-2-GFP, to track CL dynamics at membrane-level resolution using 3D structured illumination microscopy. This approach supports earlier studies that describe increased CL OMM localization in response to LPS. Our data suggest an underappreciated role for CL in macrophage responses to MRSA infection.
TPL2 kinase action and control of inflammation
Authors: Xu Daqi , Kwon Youngsu , Senger Kate , Pham Victoria , Varfolomeev Eugene , Francis George , Hackney Jason , Parr Brendan , Rathore Nisha , Setiadi Francesca , Boenig Gladys , Harris Seth , Lupardus Patrick , Matsumoto Marissa , Wang Yuanyuan , Hanson Jesse , Maher Jonathan , Wu Kai , Shaw Andrey , Scherl Alexis , Wu Jiansheng , Lu Cheng , Huang Zhiyu , Zhang Juan , Park Summer , Sujatha-Bhaskar Swathi , Almazan Alice , Xu Min , Caplazi Patrick , Brightbill Hans , Ghilardi Nico , Townsend Michael , Lee Wyne , Johnson Adam , McKenzie Brent , Zarrin Ali A , Wilson Mark 
Published: January 2023

Abstract
Tumor progression locus 2 (TPL2; also known as MAP3K8) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activates the MAPKs extracellular signal–regulated kinase 1 (ERK1) and ERK2 (ERK1/2). We describe an additional conserved and critical role for TPL2 in mediating the effector functions of myeloid cells including neutrophils, macrophages, and microglia through the activation of the p38 MAPK signaling pathway. Gene expression profiling and functional studies of neutrophils and monocytes revealed a MEK1/2-independent branch point downstream of TPL2 in neutrophils. Genetic ablation of the catalytic activity of TPL2 or therapeutic intervention with TPL2-specific inhibitors reduced inflammatory responses in vitro and in vivo. Besides myeloid cells, TPL2 also plays critical roles in fibroblast synoviocytes, indicating a potential role in rheumatoid arthritis via stromal cells.
TLR-TRIF signaling induces GLI3 to modulate inflammation
Authors: Matissek Stephan Josef , Koeppen Katja , Elsawa Sherine F 
Published: January 2023

Abstract
Chronic inflammation is associated with several disorders and therefore the identification of novel regulators of inflammation is needed. We identified GLI3 as a novel component of the TLR-TRIF signaling. Stimulation of monocytes with LPS increased GLI3 expression in a hedgehog-independent mechanism. We stimulated cells with MPLA, (TLR4 ligand that signals through TRIF) and polyI:C (TLR3 ligand) and found that IRF3 directly binds to the GLI3 promoter and IRF3 increased GLI3 expression. We generated a conditional knockout (cko) mouse where GLI3 was deleted in myeloid cells using LysM-Cre mediated recombination. IFA-elicited macrophages from cko mice stimulated with LPS showed reduced IL-6, CCL2 and TNF-a secretion compared to macrophages from wild-type (wt) littermates. We also performed RNA sequencing of LPS treated or untreated macrophages from GLI3 cko or wt mice. Using a generalized linear model in edgeR, we identified 495 genes with significant interaction effects between genotype and LPS treatment. Ingenuity Pathway Analysis of the interaction genes revealed “Inflammatory Response” and “Immune Cell Trafficking” pathways as most significantly enriched. The 25 significant interaction genes on these pathways included 9 with a positive interaction (Ccl25, Cd226, Cgas, Hmgn5, Il12b, Lrrc8a, Rapgef3, Rnf122, and Tlr8) and 16 with a negative interaction (Acacb, Adipoq, Ccl1, Ccne1, Cx3cl1, Fry, Gstk1, Mertk, Nqo2, Slc6a4, Sort1, Timd4, Tnfrsf18/GITR, Tnfsf13/APRIL, Tnfsf13b/BAFF, and Trem2). Taken together, these results identify a novel role for GLI3 in mediating TLR-TRIF-induced inflammation and identify a novel set of inflammatory genes that are dependent on GLI3 in response to TLR-TRIF signaling.
Autophagy-related protein VPS34 controls the homeostasis and function of macrophages
Authors: Yang Guan , Song Wenqiang , Postoak J. Luke , Martinez Jennifer , Zhang Jianhua , Wu Lan , Van Kaer Luc 
Published: January 2023

Abstract
Vacuolar protein sorting 34 (VPS34; also known as PIK3C3) plays a role in both canonical and noncanonical autophagy, key processes that control immune cell responsiveness to a variety of stimuli. Our previous studies found that VPS34 is a critical regulator that controls the development, homeostasis, and function of dendritic cells and T cells. In this study, we investigated the role of VPS34 in macrophage biology using myeloid cell-specific Vps34-deficient mice. We found that Vps34-deficient macrophages express increased surface levels of MHC class I and class II molecules. Interestingly, Vps34 ablation in macrophages caused a partial impairment in the homeostatic maintenance of TIM-4+ macrophages and defective uptake of apoptotic cells. In addition, myeloid cell-specific Vps34-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis (EAE), a primarily CD4+ T cell-mediated mouse model of multiple sclerosis. Importantly, peritoneal macrophages from mice deficient in the VPS34-associated protein RUBICON, which is critical for a noncanonical form of autophagy called light chain (LC) 3-associated phagocytosis (LAP), showed normal MHC class I, MHC class II, and TIM-4 expression and Rubicon−/− mice developed signs of EAE similar to wild-type control mice. These results suggested that the canonical autophagy-dependent activities of VPS34 play a critical role in controlling macrophage homeostasis and function. Collectively, our studies establish VPS34 as an important regulator of macrophage functions and macrophage-mediated regulation of EAE. Our findings also have important implications for the development of small-molecule inhibitors of VPS34 for therapeutic purposes.