bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a conserved regulatory network underlying the differentiation of immunosuppressive human macrophage
Authors: Bayik Defne , Tross Debra , Klinman Dennis M 
Published: January 2023

Abstract
There is considerable interest in generating human macrophage capable of down-modulating over-exuberant immune responses that characterize inflammatory and autoimmune diseases. Historically referred to as ‘M2-like’, macrophage with suppressive activity are conventionally generated by treating human monocytes with macrophage colony-stimulating factor (M-CSF). Unfortunately, the pleiotropic effects of M-CSF prevent it from being used therapeutically. This work identifies the TLR2/1 agonist Pam3CSK4 (hereafter PAM3) as being unique among TLR agonists in replicating the ability of M-CSF to induce monocytes to differentiate into immunosuppressive macrophage. The macrophage generated by PAM3 or M-CSF suppressed the proliferation of activated T cells and endocytosed particles with high efficiency. Consistent with their functional activity, these macrophage up-regulated expression of the surface markers DC-SIGN, SR-A and PD-L2, and secreted the anti-inflammatory mediators IL-1RA and IL-10. To clarify the pathway(s) by which macrophage with these properties arise, the regulatory networks activated by PAM3 and M-CSF were examined. NF-κB and Akt were central to the general process by which monocytes differentiate into macrophage, as their blockade prevented such maturation. By comparison, the Erk1/2 and p38 MAPK pathways were specifically involved in the differentiation of monocytes into macrophage with immunosuppressive activity. These findings identify targetable pathways to modulate the generation of immunosuppressive macrophage and demonstrate the potential utility of PAM3 for the treatment of chronic inflammation and autoimmunity.
Modulation of autophagy via lentivirus-derived shAtg5 ameliorates lupus-like disease in mice
Authors: Liu Chi-Jui , Sun Kuang-Hui 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of anti-nuclear antibodies. Traditionally, immunosuppressive and cytotoxic agents were widely used to treat lupus. However, the side effect and toxicities are inevitable. Autophagy is a process which can degrade the aged organelles and unfolded proteins to maintain the cell homeostasis. Previous studies have shown that autophagy levels were positively correlated with disease severity and elevated in B and T cells of lupus-prone mice and lupus patients. Furthermore, autophagy is essential for plasma cell differentiation, survival and antibody production. These results implicate that autophagy may promote lupus progression through regulating the survival of autoreactive immune cells. Therefore, we aim to modulate the autophagy of lupus-prone mice by lentivirus-derived shRNA targeting Atg5, an essential protein for autophagy. First, we found that levels of autophagy in splenocytes and lymphocytes of peripheral blood (PB) were elevated and positively correlated with disease severity in lupus-prone mice. The shAtg5-lentivirus, which can effectively inhibit autophagy in vitro, were then i.p. injected into TREM-1−/−. lpr mice. Mice treated with shAtg5-lentivirus exhibited lower levels of proteinuria, serum anti-dsDNA antibody and B-cell activating factor (BAFF). Lymphadenopathy as well as autophagy levels in lymph node cells and PB lymphocytes were decreased following Atg5 suppression. We also found numbers of plasma cells, CD4−CD8−, and CD4+T cells were decreased in mice treated with shAtg5-lentivirus. Thus, inhibition of autophagy may suppress immune cell expansion in lupus-prone mice and provide a novel target therapy for SLE.
Apoptotic cell driven ROS burst drives AhR dependent immunologic tolerance and suppression of lupus
Authors: Shinde Rahul Suresh , Hezaveh Kebria , Utsch Lara , Lamorte Sara , Ravishankar Buvana , Liu Haiyun , Chaudhary Kapil , Medina Tiago , Kloetgen Andreas , Halaby Marie Jo , Madaio Michael , Wither Joan , Tsirigos Aristotelis , De Carvalho Daniel , Munn David , McGaha Tracy 
Published: January 2023

Abstract
Tissue-resident macrophages (MΦ) are crucial in driving tolerance and preventing systemic autoimmunity. We have previously shown that exposure to apoptotic cells triggers a regulatory circuit dependent on IL-10 production in resident MΦ. However, key molecular mechanisms driving the regulatory response to apoptosis are not clear. RNA transcriptome analysis of MΦs after exposure to apoptotic cells identified strong transcript association with the aryl hydrocarbon receptor (AhR) signaling pathway, an association that was confirmed by phenotypic and biochemical analysis. When AhR activity was blocked, apoptotic cells induced an alteration in the mRNA signature enhancing proinflammatory effector expression. Functional analysis revealed that the DNA from apoptotic cells activated AhR in a reactive oxygen species (ROS) dependent mechanism and AhR is required for IL-10 production. Consequently, inhibition or deletion of AhR signals fundamentally altered immune responses to apoptotic cells in vivo resulting in proinflammatory cytokine production, increased effector T cell responses, and failure of long-term tolerance to apoptotic cell-associated antigens. Surprisingly, mice lacking AhR developed progressive systemic autoimmunity characterized by excessive MΦ and lymphocyte activation and renal pathology. Similarly, SLE-prone mice treated with AhR antagonist exhibited poor survival, while agonist treatment ablated disease pathology. Finally, an AhR transcriptional signature was significantly associated with active SLE flare in SLE patients. Thus, the data demonstrates the AhR pathway is a key molecular circuit responsible for apoptotic cell driven tolerance and suppression of inflammatory autoimmunity.
Kallikrein-kinin system and Type I Interferons in Neurolupus
Authors: Sriram Uma , Zuluaga-Ramirez Viviana , Merkel Steven Franklin , Winfield Malika , Fernandes Nicole C , Gajghate Sachin , Gallucci Stefania , Persidsky Yuri 
Published: January 2023

Abstract
Neuropsychiatric lupus is one of the most common manifestations of human systemic lupus erythematosus (SLE), causing depression in many. SLE is an autoimmune disease characterized by multi-organ damage including the brain and Interferon-α (IFN-α) is a central mediator in disease pathogenesis. Excessive production/response to Type I IFNs in SLE (called the “IFN signature”) is a hallmark of the disease. The mechanism of how IFN causes depression remain poorly understood; however, it is known that administration of IFN-α in certain chronic viral infections and some cancers causes the development of depressive symptoms in a high percentage of patients. The Kallikrein-Kinin System (KKS) that is comprised of kallikreins (klks), bradykinins (bk), angiotensin converting enzyme (ACE), and many other molecules, has classically known to be involved in a variety of physiological processes, including coagulation, angiogenesis and control of blood pressure. The KKS has been explored recently for their regulation of brain functions. We hypothesize that IFN-α may cause some of the symptoms in neurolupus patients and the KKS can ameliorate these effects. In this study, we used the MRL/lpr lupus-prone mouse model and showed that exposing MRL mice to IFN-α (a) increased depressive-like behavior, (b) decreased klk expression, and (c) enhanced ACE expression in the brain. Administering captopril (a commonly prescribed ACE inhibitor) decreased IFN-induced gene expression in the brain. It is also known that ACE activity decreases BK levels. The role of key KKS effectors and their interactions with the IFN pathway may provide a rationale for therapeutic use of KKS molecules for treatment of neurolupus.
Adenosine DeAminase (ADA) as an adjuvant molecule for human HIV-1 vaccine
Authors: TARDIF Virginie , Gary Ebony , Muir Roshell , Chakhtoura Marita , Cubas Rafael , Metcalf Talibah , Kutzler Michele , Haddad Elias K 
Published: January 2023

Abstract
Follicular helper T cells (Tfh) play critical role in shaping, instructing, and initiating T-cell dependent antibody responses. Understanding the underlying mechanisms that enhance their function is therefore critical for vaccine development. Using a unique gene array analysis, we have identified adenosine deaminase (ADA), as a novel key molecule that drives Tfh helper program in proliferating Germinal Centers Tfh (GC Tfh) and circulatory Tfh (cTfh) cells following their interactions with B cells. In fact, our gene array analysis showed that CD26 and ADA were exclusively up-regulated within the less efficient cTfh1 (CD4+CD45RA−CXCR5+CXCR3+) and cTfh2-17 (CD4+CD45RA−CXCR5+CXCR3+CCR6+/−) subsets, respectively. ADA enzymatic activity is significantly higher, as well, in cTfh2-17 than in the less-efficient cTfh1 cells. Exogenous ADA enhances the ability of Tfh cells to provide B cell help while inhibition of ADA activity by specific inhibitors impeded Tfh function and blunted antibody response. Our results further demonstrated that enhancement of Tfh function by ADA pathway could be due to increase in IL-6 and decrease in IL-2 production in the co-culture, and maintenance of low extracellular expression of CD26. Moreover, blocking IL-2 in cTfh2-17 co-culture from virally suppressed HIV subjects (ST) showed a significant decrease of CD26 expression associated with a rescued helper capacity. Finally, in vivo use of recombinant ADA as an adjuvant in a DNA based HIV vaccine enhanced Tfh cells differentiation and enhanced anti-Env humoral response and isotype class-switch.
Thus, ADA activity fine-tunes Tfh helper program and deciphering how ADA regulate the function of Tfh subsets would benefit future vaccine adjuvant design.
Vaccine-induced temporal cross-talk between myeloid cells reduces the risk of SIVmac251 acquisition
Authors: Vaccari Monica , Gordon Shari N , Fourati Slim , Brown Dallas , Bissa Massimiliano , Doster Melvin N , Keele Brandon K , Schifanella Luca , Lyianage N , Foulds Kathryn , Roederer Mario , Venzon David , Felber Barbara K. , Rosati Margherita , Pavlakis George N , Barouch Dan H , Sekaly Rafick P , Franchini Genoveffa 
Published: January 2023

Abstract
Vaccination with recombinant ALVAC + gp120 alum boosts has decreased the risk of acquisition of HIV/SIV in humans and in macaques. We tested whether the substitution of the first ALVAC-SIV immunization with either a DNA- or an Ad26-based SIV vaccine would affect vaccine efficacy. We found that the DNA prime was associated with 52% vaccine efficacy whereas the Ad26 prime regimen was ineffective.
The two primes differently altered the monocytes levels of CD14+DR+ classical monocytes and myeloid-derived suppressor cells (MDSC) in blood. The DNA resulted in a more pronounced expansion of CD14+DR+ than the Ad26 prime. In this group the frequency of classical monocytes was associated with higher levels of SIV specific CD4+ T cell responses and delayed SIVmac251 acquisition, whereas MDSC correlated with lower levels of T cell responses and early acquisition. Accordingly, plasma levels of arginase, an enzyme produced by MDSC and linked to the suppression of immune responses, also correlated with early SIVmac251 acquisition. Systems biology studies revealed a correlation between the expression of distinct gene expression signatures associated to monocytes which correlated either with acquisition or protection.
Altogether these data indicate that the priming may shape the cross-talk between monocytes and MDSCs and highlights the importance of vaccine induced innate responses in protection from virus acquisition.
Efficacy and immunogenicity of a novel polyanhydride nanovaccine for use against RSV infection in the neonate
Authors: McGill Jodi L , Kelly Sean , Narasimhan Balaji , Henningson Jamie , Kumar Pankaj , Sacco Randy E 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is a leading cause of severe acute lower respiratory tract infection in infants and children worldwide. Bovine RSV (BRSV) is closely related to human RSV and a significant cause of morbidity in young cattle. BRSV infection in calves displays many similarities to RSV infection in humans, including similar age dependency, gross and microscopic pathology, and innate and adaptive immune responses. The poor immunogenicity of RSV has been a complicating factor in the development of a safe and effective vaccine in both humans and calves. Polyanhydride nanovaccines (i.e. nanoparticle-based vaccines) have shown promise as adjuvants and vaccine delivery vehicles in rodent models due to their ability to promote enhanced immunogenicity through both the route of administration and the ability to provide sustained antigen exposure. In these studies, we determined the efficacy of a novel polyanhydride nanovaccine containing the stable, post-fusion F and G glycoproteins from BRSV, against RSV infection using a neonatal calf model. In vitro, the BRSV nanovaccine induced activation and cytokine secretion by monocyte-derived dendritic cells and alveolar macrophages. In vivo, calves receiving the BRSV F/G nanovaccine, followed by aerosol challenge with BRSV, demonstrated increased virus-specific IgA in the nasal and bronchoalveolar lavage fluid, an increase in RSV-specific cellular responses in the peripheral blood and airways, and a reduction in BRSV shedding compared to unvaccinated control calves. Our results suggest that the RSV-F/G nanovaccine is highly immunogenic and with optimization, has the potential to significantly reduce the disease burden associated with RSV infection in both humans and animals.
Understanding fetal immune responses to congenital porcine reproductive and respiratory syndrome virus infection
Authors: Venner Laura C , Hong Linjun , Ladinig Andrea , Harding John C S , Lunney Joan 
Published: January 2023

Abstract
Porcine Reproductive and Respiratory Syndrome (PRRS) is one of the most economically significant diseases in the global swine industry, causing late-term abortions, early farrowing, and respiratory disease. Few studies have previously explored the immune pathways that alter fetal PRRS resistance/ susceptibility. Using a model where 3rd trimester pregnant gilts were euthanized at 2, 5, 8, 12, or 14 days post infection (DPI) with PRRS virus (PRRSV), samples from the fetal thymus and placenta, and maternal endometrium were collected and viral loads measured (U Saskatchewan) to determine when the virus crosses the placental barrier and infects each fetus. RNA was extracted with a Qiagen RNA Isolation kit, and gene expression determined using a 220 gene NanoString array to evaluate differential expression (DE) of genes and biomarkers previously predicted to alter PRRS resistance and susceptibility. Selected biomarkers that were measured included interferon signaling pathways, TREM1, HMGB1, B and T cell receptors, cell division, apoptosis, tissue remodeling and epithelial integrity, based on pathways identified using Ingenuity Pathway Analysis. Fetuses from the control gilt will be compared to those from three PRRSV infected gilts from the same DPI based on serum and thymus viral levels, comparing their viral negative (uninfected) and viral positive (infected) fetuses from the same litter. Comparisons of DE genes will be made between neighboring fetuses and across DPI. Data should reveal immunological pathways that contribute to fetal susceptibility. Understanding these mechanisms will benefit future research dedicated to exploring targeted approaches to halt the congenital spread of this disease.
Equine B lymphocytes exhibit TLR4 expression similar to humans
Authors: Kasmark Leah , Wagner Alayna , Zhu Jing , Creger Lindsay , Leeth Caroline McPhee 
Published: January 2023

Abstract
Toll-like receptor 4 (TLR4) is a well-documented Toll-like receptor that recognizes bacterial lipopolysaccharide (LPS) as its ligand. Expression of TLR4 has been well described in murine and human B cells. Murine B lymphocytes have relatively constant TLR4 expression, where in humans, expression is present, but low. However, systemically mice show low sensitivity to LPS and humans show high sensitivity. Horses share this high sensitivity to LPS with humans. Here, we look at TLR4 presence and activation in equine B lymphocytes. Research in this area has been hampered due to the lack of quality B lymphocyte markers. Anti-human CD21 was previously found to mark peripheral equine B cells. We show CD45R (B220) also accurately labels equine B lymphocytes. We also demonstrate TLR4 is expressed on equine B lymphocytes using the TLR4 antibody, clone 76B357.1. By using the density gradient, Lympholyte, equine lymphocytes can be separated out of peripheral blood and stimulated with LPS. We demonstrate equine B lymphocytes fail to proliferate under LPS challenge as opposed to highly proliferative mouse B lymphocytes. This lack of response is similar to that seen in humans and may be a clue to LPS sensitivity shared by horses and humans.
The Slam/SAP signaling pathway regulates γδ T cell effector functions
Authors: Dienz Oliver , DeVault Victoria L. , Spear Camarie C. , Mei Linda , Boyson Jonathan E 
Published: January 2023

Abstract
The Slam/SAP (SLAM-associated protein) signaling pathway plays a central role in the host immune response to infections. Males that inherit an inactivated SAP gene develop X-linked lymphoproliferative syndrome (XLP), a serious immunodeficiency that often results in enhanced susceptibility to a variety of pathogens. SAP is a cytosolic adapter protein that transduces signals from Slam family receptors, a family of nine (SLAMf1 to SLAMf9) cell surface receptors that are expressed only on hematopoietic cells. Although the Slam/SAP axis is known to regulate the development and function of several lymphocyte subsets, their role in γδ T cell biology is less well understood. We analyzed simultaneously the expression of multiple Slam receptors on γδ T cells and observed significant heterogeneity among γδ T cell subsets. Interestingly, Slam expression patterns marked functional γδ T cell subsets in both naïve and influenza-infected mice. SLAMf6 expression on lung γδ T cells correlated with IFNγ-producing CD27+ cells while SLAMf1 expression characterized IL-17-producing CD27− RORγt+ γδ T cells. The heterogeneous Slam receptor expression patterns of γδ T cell subsets can already be seen during embryonic thymic development, suggesting a possible role in the developmental programming of γδ T cell effector function. Disruption of Slam signaling through deletion of SAP affected the development of RORγt+ CD44hi Vγ4 T cells in the embryonic thymus, and the frequency of RORγt+ Vγ4 T cells in the periphery was still diminished in the adult. These results suggest that the Slam/SAP signaling pathway is an important regulator of the functional programming γδ T cells undergo during thymic development which affects mucosal immune responses later in life.
Intracellular protein degradation of BRD4 by dBET1 reveals conserved in vivo cereblon function in human and mouse T-cells
Authors: Akuffo Afua Adutwumwa , Alontaga Aileen , Metclaf Rainer , Beatty Matthew S , McDaniel Jessica , Gunawan Steven , Ayaz Muhammad , Becker Andreas , Hesterberg Rebecca S , Goodheart William E , Yang Yan , Daniel Kenyon G , Schonbrunn Ernst , Guida Wayne , Lawrence Harshani , Lawrence Nicholas , Epling-Burnette Pearlie 
Published: January 2023

Abstract
Protein degraders have been developed that can aide in understanding gene function. These chemicals contain complementary bifunctional components that 1) interact with specific proteins, and 2) engage an E3 ligase which leads to polyubiquitination and intracellular degradation by the proteasome. Thalidomide, infamously known for its teratogenic effects, is central to this new technology since it binds cereblon (CRBN) which promiscuously recruits the DDB1/Cul4A/Rbx1 complex to trigger target destruction. Thalidomide, and especially its immunomodulatory derivatives lenalidomide and pomalidomide, induce NK and T-cell activation by degrading IKZF1 which is a transcription factor that suppresses IL-2. Currently, it is debated whether mouse cereblon has conserved function due to a single non-conserved amino acid in mouse CRBN, Ile390 (equivalent to Val388 in human CRBN). First, our work confirms that lenalidomide induces IL-2 and the ubiquitin-dependent degradation of IKZF1 only in human and not mouse T-cells treated with lenalidomide. To further test for species-related effects, a series of theoretical and physical binding assays using mutant CRBN proteins show that the binding of IMiD compounds is not impaired by amino acid differences in mouse CRBN. Using dBET1, a novel thalidomide-JQ1 protein degrader, we show for the first time that mouse CRBN can trigger CRBN-dependent degradation of BRD4 and confirm that the CRBN/DDB1/Cul4A/Rbx1 complex is functional in mouse T-cells. Collectively, our results suggest that IKZF1 has divergent regulation in mouse cells rather than the IMiD complex and provide information relevant to the development of chemical conjugates that induce targeted intracellular protein degradation.
Sodium chloride inhibits IFN-γ, but not IL-4, production by invariant NKT cells
Authors: Jeong Dongjin , Chung Doo Hyun 
Published: January 2023

Abstract
Invariant NKT (iNKT) cells are a distinct subset of T cells that exert Janus-like functions in vivo by producing IFN-γ and IL-4. Sodium chloride modulates the functions of various immune cells, including conventional CD4+ T cells and macrophages. However, it is not known whether sodium chloride affects iNKT cell function, so we addressed this issue. Sodium chloride inhibited IFN-γ, but not IL-4, production by iNKT cells upon TCR stimulation in a dose-dependent manner. Consistently, sodium chloride reduced the expression level of t-bet, but not gata-3, in iNKT cells stimulated with TCR engagement. Sodium chloride increased phosphorylated p38 expression in iNKT cells and inhibitors of p38 and NFAT5, and SGK1 restored IFN-γ production by iNKT cells stimulated with sodium chloride and TCR engagement. Furthermore, adoptive transfer of iNKT cells pretreated with sodium chloride restored antibody-induced joint inflammation to a lesser extent than for untreated iNKT cells in Jα18 knockout mice. These findings suggest that sodium chloride inhibits IFN-γ production by iNKT cells upon TCR stimulation, which is dependent on p38, NFAT5, and SGK1. These findings highlight the functional role of sodium chloride in iNKT cell-mediated inflammatory diseases.