Autoregulated splicing of β programs T cell fate in response to antigen-receptor stimulation.

T cell receptor (TCR) sensitivity to peptide-major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2β in mouse and human.

Monitoring Circulating Myeloid Cells in Peritonitis with an In Vivo Imaging Flow Cytometer.

Peritonitis is a common and life-threatening inflammatory disease. Myeloid cells are elevated in the peripheral blood and contribute to peritonitis, but their circulating dynamics are not clear. In vivo flow cytometry (IVFC) is a noninvasive technique for monitoring the dynamics of circulating cells in live animals.

Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR.

Atherosclerotic plaques are defined by the accumulation of lipids and immune cells beneath the endothelium of the arterial intima. CD8 T cells are among the most abundant immune cell types in plaque, and conditions linked to their activation correlate with increased levels of cardiovascular disease. As lethal effectors of the immune response, CD8 T cell activation is suppressed at multiple levels.

UBXN3B is crucial for B lymphopoiesis.

Background: The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity.

IRAK4 is an immunological checkpoint in neuropsychiatric systemic lupus erythematosus.

The search for dementia treatments, including treatments for neuropsychiatric lupus (NPSLE), has not yet uncovered useful therapeutic targets that mitigate underlying inflammation. Currently, NPSLE's limited treatment options are often accompanied by severe toxicity. Blocking toll-like receptor (TLR) and IL-1 receptor signal transduction by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4) offers a new pathway for intervention.

UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.

The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown.

Astrocytic TIMP-1 regulates production of Anastellin, an inhibitor of oligodendrocyte differentiation and FTY720 responses.

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global knockout () mice do not efficiently remyelinate following a demyelinating injury.

CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe's disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein, we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD.

Capturing the multifaceted function of adipose tissue macrophages.

Adipose tissue macrophages (ATMs) bolster obesity-induced metabolic dysfunction and represent a targetable population to lessen obesity-associated health risks. However, ATMs also facilitate adipose tissue function through multiple actions, including adipocyte clearance, lipid scavenging and metabolism, extracellular remodeling, and supporting angiogenesis and adipogenesis. Thus, high-resolution methods are needed to capture macrophages' dynamic and multifaceted functions in adipose tissue.

Astrocytic TIMP-1 regulates production of Anastellin, a novel inhibitor of oligodendrocyte differentiation and FTY720 responses.

Unlabelled: Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression of do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global knockout ( ) mice do not efficiently remyelinate following a demyelinating injury.

Antigen-specific downregulation of miR-150 in CD4 T cells promotes cell survival.

MicroRNA-150 (miR-150) has been shown to play a general role in the immune system, but very little is known about its role on CD4 T cell responses. During T cell responses against superantigen Staphylococcal Enterotoxin A, miR-150 expression was down-regulated in antigen-specific CD4 T cells but up-regulated in CD8 T cells. CD4 and CD8 T cell clonal expansion was greater in miR-150-KO mice than in WT mice, but miR-150 selectively repressed IL-2 production in CD4 T cells.

Interleukin-17 Promotes the Infiltration of CD8+ T Cells into the Brain in a Mouse Model for Alzheimer's Disease.

Background: Interleukin-17 (IL-17) family cytokines play critical roles in inflammation and pathogen resistance. Inflammation in the central nervous system, denoted as neuroinflammation, promotes the onset and progression of Alzheimer's disease (AD). Previous studies showed that IL-17A neutralizing antibody treatment alleviated Amyloid β (Aβ) burden in rodent models of AD, while overexpression of IL-17A in mouse lateral ventricles rescued part of the AD pathology.

Macrophages at the Crossroad of Meta-Inflammation and Inflammaging.

Macrophages are central players in systemic inflammation associated with obesity and aging, termed meta-inflammation and inflammaging. Activities of macrophages elicited by the two chronic conditions display shared and distinct patterns mechanistically, resulting in multifaceted actions for their pathogenic roles. Drastically expanded tissue macrophage populations under obesity and aging stress attribute to both enhanced recruitment and local expansion.

Nexinhib20 Inhibits Neutrophil Adhesion and β Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction.

Neutrophils are critical for mediating inflammatory responses. Inhibiting neutrophil recruitment is an attractive approach for preventing inflammatory injuries, including myocardial ischemia-reperfusion (I/R) injury, which exacerbates cardiomyocyte death after primary percutaneous coronary intervention in acute myocardial infarction. In this study, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits not only exocytosis but also neutrophil adhesion by limiting β integrin activation.

Splice factor polypyrimidine tract-binding protein 1 (Ptbp1) primes endothelial inflammation in atherogenic disturbed flow conditions.

NF-κB-mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through adhesion molecules Icam1 and Vcam1. The endothelium is primed for cytokine activation of NF-κB by exposure to low and disturbed blood flow (LDF)but the molecular underpinnings are not fully understood. In an experimental in vivo model of LDF, platelets were required for the increased expression of several RNA-binding splice factors, including polypyrimidine tract binding protein (Ptbp1).

Optimal CD8 T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape.

Boosting T cell activation through costimulation directs defense against cancer and viral infections. Despite multiple studies targeting costimulation in clinical trials, the increased potency and reprogramming of T cells endowed by costimulation is poorly understood. Canonical dogma states that transcription mediates T cell activation.

Evaluating the glycolytic potential of mouse costimulated effector CD8 T cells .

Studying the metabolic fitness of T cells is fundamental to understand how immune responses are regulated. Here, we describe a step-by-step protocol optimized to efficiently generate and isolate effector antigen-specific CD8 T cells using costimulation. We also detail steps to evaluate their metabolic activity using Seahorse technology.

Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling.

Nicotinamide (NAM) shapes T cell responses but its precise molecular mechanism of action remains elusive. Here, we show that NAM impairs naive T cell effector transition but also effector T cells themselves. Although aerobic glycolysis is a hallmark of activated T cells, CD8 T cells exposed to NAM displayed enhanced glycolysis, yet producing significantly less IFNγ.

Concentration of vaginal and systemic cytokines obtained early in pregnancy and their impact on preterm birth.

Objective: A number of factors can lead to a maternal pro-inflammatory response resulting in a spontaneous preterm birth. However, it remains unknown if an upregulation in the maternal immune system early in pregnancy leads to an increase in pro-inflammatory cytokines and ultimately preterm birth. Therefore, we hypothesize an increase in vaginal and systemic pro-inflammatory cytokines early pregnancy is associated with an increased risk of preterm birth.

AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk.

Background: Whereas several interventions can effectively lower lipid levels in people at risk for atherosclerotic cardiovascular disease (ASCVD), cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to cardiovascular event risk. Monocytes and macrophages play central roles in atherosclerosis, but studies have yet to provide a detailed view of macrophage populations involved in increased ASCVD risk.

Methods: A novel macrophage foaming analytics tool, AtheroSpectrum, was developed using 2 quantitative indices depicting lipid metabolism and the inflammatory status of macrophages.

An Essential Role of UBXN3B in B Lymphopoiesis.

Hematopoiesis is finely regulated to enable timely production of the right numbers and types of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential role of UBXN3B in maintenance of hematopoietic homeostasis and restriction of immunopathogenesis during respiratory viral infection.

UBX Domain Protein 6 Positively Regulates JAK-STAT1/2 Signaling.

Type I/III IFNs induce expression of hundreds of IFN-stimulated genes through the JAK/STAT pathway to combat viral infections. Although JAK/STAT signaling is seemingly straightforward, it is nevertheless subjected to complex cellular regulation. In this study, we show that an ubiquitination regulatory X (UBX) domain-containing protein, UBXN6, positively regulates JAK-STAT1/2 signaling.

Granulocyte-macrophage colony-stimulating factor initiates amniotic membrane rupture and preterm birth in a mouse model.

Objective: Preterm premature rupture of membranes is associated with 30% of all preterm births. The weakening of amniotic membranes is associated with an increase in matrix metallopeptidases (MMPs) along with a decrease in their inhibitors, tissue inhibitor metallopeptidases (TIMPs). Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to weaken fetal membranes in-vitro.