A5101906216- Inflammasome and immune disorders
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immune cells in cancer
- Immune Response and Inflammation
- Phagocytosis and Immune Regulation
- Lymphoma Diagnosis and Treatment
- Immune Cell Function and Interaction
- Heme Oxygenase-1 and Carbon Monoxide
- Single-cell and spatial transcriptomics
- Redox biology and oxidative stress
- Hematopoietic Stem Cell Transplantation
- Sulfur Compounds in Biology
- Acute Myeloid Leukemia Research
- Gout, Hyperuricemia, Uric Acid
- CAR-T cell therapy research
- Zebrafish Biomedical Research Applications
- COVID-19 Clinical Research Studies
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Viral-associated cancers and disorders
- T-cell and Retrovirus Studies
- Kawasaki Disease and Coronary Complications
- Vascular Tumors and Angiosarcomas
- Adenosine and Purinergic Signaling
- Cancer Immunotherapy and Biomarkers
- PI3K/AKT/mTOR signaling in cancer
VA Boston Healthcare System
2016-2025
Harvard University
2008-2020
Veterans of Foreign Wars
2018
Brigham and Women's Hospital
2008-2017
University of Massachusetts Chan Medical School
2010-2016
UMass Memorial Medical Center
2014-2016
Phillips University
2010
Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as GSDMD-binding partner. S-palmitoylation at Cys
Abstract Both lytic and apoptotic cell death remove senescent damaged cells in living organisms. However, they elicit contrasting pro- anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil pyroptotic death. tightly regulated GSDME cleavage activation aging neutrophils are mediated by proteinase-3 caspase-3, leading to...
Candida albicans is the most common cause of fungal sepsis. Inhibition inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, signaling appears protect against C. infection, so inhibitors are not clinically useful for candidiasis. Here we show disruption GSDMD, a known target key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes survival Candida-infected mice. Mechanistically, hijacked canonical inflammasome-GSDMD...
Gasdermin D (GSDMD)-mediated macrophage pyroptosis plays a critical role in inflammation and host defense. Plasma membrane perforation elicited by caspase-cleaved GSDMD N-terminal domain (GSDMD-NT) triggers rupture subsequent pyroptotic cell death, resulting release of pro-inflammatory IL-1β IL-18. However, the biological processes leading to its translocation pore formation are not fully understood. Here, using proteomics approach, we identified fatty acid synthase (FASN) as GSDMD-binding...
Gene expression profiling identified genes uniquely expressed by human germinal-center T-helper (GCTh) cells, including programmed death-1 (PD-1) and CXCL13. Recently, we demonstrated that PD-1 is an immunophenotypic marker of GCTh cells angioimmunoblastic T-cell lymphoma (AITL). The goal this study was to investigate the pattern CXCL13 in comparison with PD-1. We studied 63 cases lymphoproliferative disorders, 22 AITL. In AITL, PD-1+ CXCL13+ neoplastic were seen at foci expanded CD21+...
Programmed cell death ligand 1 (PD-L1) is a surface glycoprotein that regulates the cellular immune response and serves as targetable checkpoint molecule. PD-L1 expressed on tumor cells microenvironment of several human malignancies, including subset aggressive lymphomas. We sought to investigate further clinical pathologic features EBV-negative diffuse large B-cell lymphoma (DLBCL) cases express PD-L1. Immunohistochemical staining using an anti-PD-L1 monoclonal antibody was performed DLBCL...
The significance of developing host-modulating personalized therapies to counteract the growing threat antimicrobial resistance is well-recognized because such cannot be overcome using microbe-centered strategies alone. Immune host defenses must finely controlled during infection balance pathogen clearance with unwanted inflammation-induced tissue damage. Thus, an ideal treatment would enhance bactericidal activity while preventing neutrophilic inflammation, which can induce We report that...
Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function extracellular components via unknown. Using screening approach, we identified ROS-mediated on several cytokines. Glutathionylation highly conserved Cys-188 in IL-1β positively regulates its bioactivity by preventing ROS-induced irreversible oxidation,...
Abstract Both microbial infection and sterile inflammation augment bone marrow (BM) neutrophil production, but whether the induced accelerated granulopoiesis is mediated by a common pathway nature of such are poorly defined. We recently established that BM myeloid cell–derived reactive oxygen species (ROS) externally regulate progenitor proliferation differentiation in bacteria-elicited emergency granulopoiesis. In this article, we show ROS levels also elevated during inflammation. Similar...
Survival of neutrophils is prolonged, and their function preserved by simultaneously targeting multiple cell death pathways.
Hematopoietic stem and progenitor cells (HSPCs) undergo self-renewal differentiation to guarantee a constant supply of short-lived blood cells. Both intrinsic extrinsic factors determine HSPC fate, but the underlying mechanisms remain elusive. Here, we report that Proteinase 3 (PR3), serine protease mainly confined granulocytes, is also expressed in HSPCs. PR3 deficiency intrinsically suppressed cleavage activation caspase-3, leading expansion bone marrow (BM) population due decreased...
The need for accurate antibody testing in patients following symptomatic or asymptomatic infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented. How we best utilize the data obtained from these studies still a haunting question (1). There are now over 160 serologic kits on market detection of antibodies to this virus (2). Most not Emergency Use Authorization (EUA)/FDA approved, and due poor performance some assays, FDA has requested more stringent In...
Reactive oxygen species (ROS)‐induced Cysteine S‐glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function extracellular components via remains elusive. Here using screening approach, we identified ROS‐mediated cysteine on several cytokines. Glutathionylation positively regulated IL‐1β bioactivity highly conserved Cys‐188 residue by preventing its...
Abstract Gasdermin D (GSDMD) is considered a pro-inflammatory factor that mediates pyroptosis in macrophages to protect hosts from intracellular bacteria. Here we reveal GSDMD deficiency paradoxically augmented host responses extracellular Escherichia coli, mainly by delaying neutrophil death, establishing as negative regulator of innate immunity. In contrast its activation macrophages, which activated inflammatory caspases cleave produce an N-terminal fragment (GSDMD-cNT) trigger...
Pathogen-initiated chronic inflammation or autoimmune diseases accelerate proliferation and promote differentiation of hematopoietic stem cells (HSCs) but simultaneously reduce reconstitution capacity. Nevertheless, the effect acute infection on functional HSCs is still largely unknown. Here we found that elicited by heat-inactivated Escherichia coli (HIEC) expanded bone marrow lineage-negative (Lin)- stem-cell antigen 1 (Sca-1)+cKit+ (LSK) cell population, leading to reduced frequency in...
Gasdermin D (GSDMD) is considered a pro-inflammatory factor that mediates lytic pyroptotic cell death in macrophages to protect hosts from intracellular bacteria (He et al., 2015; Kayagaki Shi 2015a). However, GSDMD’s role clearing extracellular pathogens has not been directly examined. Here we reveal GSDMD deficiency unexpectedly and paradoxically augmented host responses Escherichia coli, mainly by delaying neutrophil death, for the first time establishing as negative regulator of innate...
Hematopoietic ontogeny consists of two broad programs: an initial hematopoietic stem cell (HSC)-independent program arising from the yolk sac followed by HSC-dependent hematopoiesis intra-embryonic arteries. While HSC-independent erythro-myeloid (EMP) progenitors and rare lymphoid progenitors, as well HSCs, sequentially seed fetal liver generate blood cells, transition to HSC-derived remains poorly characterized. To help resolve this question, we developed Mds1CreER mice, which inducibly...