A5078809930- Cytokine Signaling Pathways and Interactions
- Systemic Lupus Erythematosus Research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- interferon and immune responses
- RNA Research and Splicing
- Immune Response and Inflammation
- Estrogen and related hormone effects
- NF-κB Signaling Pathways
- Immunotherapy and Immune Responses
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- RNA Interference and Gene Delivery
- Immune cells in cancer
- Phagocytosis and Immune Regulation
- Osteoarthritis Treatment and Mechanisms
- Cancer-related gene regulation
- Reproductive System and Pregnancy
- Mitochondrial Function and Pathology
- Redox biology and oxidative stress
- DNA and Nucleic Acid Chemistry
- Monoclonal and Polyclonal Antibodies Research
- Orthopaedic implants and arthroplasty
Hospital for Special Surgery
2014-2025
New York Proton Center
2024
Cornell University
2005-2011
Carnegie Institution for Science
2003
University of Michigan
2000-2003
Howard Hughes Medical Institute
2000-2003
University of Missouri
1996-2000
The kinetics and magnitude of cytokine gene expression are tightly regulated to elicit a balanced response pathogens result from integrated changes in transcription mRNA stability. Yet, how single microbial stimulus induces peak some genes (TNFalpha) within minutes whereas others (IP-10) require hours remains unclear. Here, we dissect activation several lipopolysaccharide (LPS)-inducible macrophages, an essential cell type mediating inflammatory mammals. We show that key difference between...
Type I interferon (IFN) is essential for host defenses against viruses; however, dysregulated IFN signaling causally linked to autoimmunity, particularly systemic lupus erythematosus. Autoimmune disease treatments rely on glucocorticoids (GCs), which act via the GC receptor (GR) repress proinflammatory cytokine gene transcription. Conversely, through cognate Jak/STAT pathways reportedly unaffected or even stimulated by GR. Unexpectedly, we found that GR dramatically inhibited IFN-stimulated...
Abstract Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c + T-bet critical for antiviral disorders. Absence DEF6 SWAP-70, two homologous guanine exchange factors, double-knock-out (DKO) mice leads lupus-like syndrome females marked by accumulation ABCs. Here we demonstrate that DKO ABCs sex-specific differences cell number, upregulation an ISG...
Inflammation triggered by infection or injury is tightly controlled glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, hierarchy transcriptional responses GR activation and molecular basis their oftentimes non-linear dynamics are not understood. We investigated early glucocorticoid-driven events in macrophages, cell type highly responsive both pro- anti-inflammatory stimuli. Using whole...
Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is key component anti-inflammatory actions glucocorticoids, yet underlying molecular mechanisms remain obscure. Here we report that repression genes in primary macrophages mediated GR-interacting protein (GRIP)1, a transcriptional coregulator p160 family, which recruited to p65-occupied genomic NFκB-binding sites conjunction with liganded GR. We created mouse strain enabling conditional hematopoietic...
Significance Male-biased inequality in Imperial China imposed strong limitations on the economic and intellectual contribution of women to society fostered male-biased resource distribution, because females were subordinated priorities patriarchal state. Analyzing human skeletal remains from early agricultural later preimperial archaeological sites, we find no evidence between males farming communities. The observed differences male female skeletons Eastern Zhou contexts allow us infer a...
Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α heparin-binding EGF (HB-EGF), have been implicated the pathogenesis chronic kidney diseases. Here, we demonstrate that deficiency iRhom2 protects lupus-prone Fcgr2b–/– mice from developing severe damage without altering anti-double-stranded DNA (anti-dsDNA) Ab production by...
<h3>Objectives</h3> Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis autoimmune disorders such as systemic lupus erythematosus (SLE) rheumatoid arthritis (RA). Production IL-17 can be regulated by ROCK2, one two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated activity a new cohort, RA assessed ability distinct inhibitors pathway suppress T cells or human Th17 cells. <h3>Methods</h3> peripheral blood...
The glucocorticoid receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early arrest, non-paused induced by de novo Pol2 recruitment, are equally susceptible to acute repression. Moreover, both cases dominant mechanism involves rapid...
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin metalloprotease 17 (ADAM17)-mediated release epidermal growth factor receptor (EGFR) ligands LC ADAM17 sheddase activity reduced in lupus. Here, we sought understand how the...
Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the receptor (GR), a ligand-dependent transcription factor nuclear superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to DNA-bound activator and NF-κB represses their target proinflammatory cytokine genes. However, these genes fall into distinct classes depending on step cycle that is rate-limiting for activation: Some controlled through RNA polymerase II (PolII)...
Post-transcriptional modifications can control protein abundance, but the extent to which these alterations contribute expression of T helper (TH) lineage-defining factors is unknown. Tight regulation Bcl6 expression, an essential transcription factor for follicular (TFH) cells, critical as aberrant TFH cell expansion associated with autoimmune diseases, such systemic lupus erythematosus (SLE). Here we show that lack SLE risk variant Def6 results in deregulation synthesis cells a result...
The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here we demonstrate ROCK1 regulates differentiation in hostile environments replete with PAMPs (pathogen-associated molecular patterns) and high levels of heme controlling two key heme-regulated molecules, BACH2 Heme-regulated eIF2a kinase (HRI). phosphorylates protects it from heme-driven...
Abstract Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory WAT-resident macrophages counteract resistance, yet, the mechanisms underlying transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor—glucocorticoid (GR)-interacting protein...
Abstract Autologous blood-derived products such as platelet-rich plasma (PRP) are widely used to treat musculoskeletal conditions, including knee osteoarthritis (OA). However, the clinical outcomes after PRP administration often variable, and there is limited information about specific characteristics of that impact bioactivity responses. In this study, we aimed develop an integrative workflow evaluate responses in vitro, assess if vitro associated with composition patients OA. To do this, a...
Abstract Studies on macrophage gene expression have historically focused events leading to RNA polymerase II recruitment and transcription initiation, whereas the contribution of post-initiation steps activation remains poorly understood. Here, we report that widespread promoter-proximal pausing in resting macrophages is marked by co-localization negative elongation factor (NELF) complex facilitated PU.1. Upon inflammatory stimulation, over 60% activated transcriptome regulated pause-release...