A5076702626- Immune Response and Inflammation
- NF-κB Signaling Pathways
- Immunotherapy and Immune Responses
- Gut microbiota and health
- Immune Cell Function and Interaction
- Cytokine Signaling Pathways and Interactions
- T-cell and B-cell Immunology
- Clostridium difficile and Clostridium perfringens research
- Lymphatic System and Diseases
- Immune cells in cancer
- Mycobacterium research and diagnosis
- Hematopoietic Stem Cell Transplantation
- Cell Adhesion Molecules Research
- Lymphoma Diagnosis and Treatment
- Pancreatic function and diabetes
- interferon and immune responses
- Circadian rhythm and melatonin
- Monoclonal and Polyclonal Antibodies Research
- Chronic Lymphocytic Leukemia Research
- Inflammatory mediators and NSAID effects
- Renal Transplantation Outcomes and Treatments
- Cancer Immunotherapy and Biomarkers
- Atherosclerosis and Cardiovascular Diseases
- Neonatal Respiratory Health Research
- Pediatric health and respiratory diseases
University of Maryland, Baltimore
2015-2025
University of Mary
2022
Center for Vascular Biology Research
2018
University of Maryland, College Park
2013
Medizinische Hochschule Hannover
2003-2010
St. Joseph's Hospital and Medical Center
2007
Barrow Neurological Institute
2007
Peking University
2004
TLRs activate immune responses by sensing microbial structures such as bacterial LPS, viral RNA, and endogenous "danger" molecules released damaged host cells. MyD88 is an adapter protein that mediates signal transduction for most leads to activation of NF-kappaB MAPKs production proinflammatory cytokines. TLR4-mediated signaling also rapid PI3K, one a family kinases involved in regulation cell growth, apoptosis, motility. LPS stimulates phosphorylation Akt, downstream target wild-type (WT)...
Abstract Current immunosuppressants effectively suppress adaptive and innate immune responses, but their broad, antigen-non-specific effects often result in significant complications. Here, we conducted a systematic investigation of drug on gut microbiome, metabolic pathways, lymphoid architecture lymphocyte trafficking four major classes including tacrolimus, prednisone, mycophenolate mofetil (MMF), Fingolimod (FTY). We show that induced progressive alterations the microbiome where initial...
In this study, we examined whether tyrosine phosphorylation of the Toll-IL-1 resistance (TIR) domain Toll-like receptor (TLR) 4 is required for signaling and blocked in endotoxin tolerance. Introduction P712H mutation, responsible lipopolysaccharide (LPS) unresponsiveness C3H/HeJ mice, into TIR constitutively active mouse ΔTLR4 mutation homologous P714 human CD4-TLR4 rendered them signaling-incompetent TLR4 phosphorylation. Mutations residues Y674A Y680A within domains impaired its ability...
Proteinase-activated receptor 2 (PAR2), a seven-transmembrane G protein-coupled receptor, is activated at inflammatory sites by proteolytic cleavage of its extracellular N terminus trypsin-like enzymes, exposing tethered, receptor-activating ligand. Synthetic agonist peptides (AP) that share the tethered ligand sequence also activate PAR2, often measured Ca2+ release. PAR2 contributes to inflammation through activation NF-κB-regulated genes; however, mechanism which this occurs unknown....
Asp(299)Gly (D299G) and, to a lesser extent, Thr(399)Ile (T399I) TLR4 polymorphisms have been associated with gram-negative sepsis and other infectious diseases, but the mechanisms by which they affect signaling are unclear. In this study, we determined impact of D299G T399I on expression, interactions myeloid differentiation factor 2 (MD2), LPS binding, LPS-mediated activation MyD88- Toll/IL-1R resistance domain-containing adapter inducing IFN-β (TRIF) pathways. Complementation human...
Sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) regulate migration of lymphocytes out thymus to blood lymph nodes (LNs) efferent lymph, whereas their role in other tissue sites is not known. Here, we investigated the question how these molecules leukocyte from tissues through afferent lymphatics draining LNs (dLNs). S1P, but chemokines, selectively enhanced human murine CD4 T cell across lymphatic endothelial cells (LECs). S1PR1 S1PR4, LEC S1PR2, were required for LECs into vessels...
Abstract Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration there contradictory data roles regulatory (Treg) function. Here we show activated Tregs CD4 effector cells (Teffs) use PD-1/PD-L1 CD80/PD-L1, respectively, to transendothelial across lymphatic endothelial (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative for PD-L1), or LEC impairs vitro vivo. signals...
Abstract Endotoxin tolerance interferes with TLR4 signalosome assembly, kinase/transcription factor activation, and increases negative TLR pathway regulators. reprograms cell responses to LPS by repressing expression of proinflammatory cytokines, while not inhibiting production anti-inflammatory cytokines antimicrobial effectors. Molecular mechanisms induction maintenance endotoxin are incompletely understood, particularly regard the impact tolerization on activation adaptor-kinase modules,...
Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) activate G protein–coupled receptors (GPCRs) to regulate biological processes. Using a genome-wide CRISPR/dCas9–based GPCR signaling screen, LPAR1 was identified as an inducer of S1PR1/β-arrestin coupling while suppressing Gαi signaling. S1pr1 Lpar1-positive lymphatic endothelial cells (LECs) lymph nodes exhibit constitutive signaling, which suppressed by antagonism. Pharmacological inhibition or genetic loss function Lpar1...
Abstract The beneficial effects attributed to Bifidobacterium are largely their immunomodulatory capabilities, which likely be species- and even strain-specific. However, strain-specificity in direct indirect immune modulation remain uncharacterized. We have shown that B. pseudolongum UMB-MBP-01, a murine isolate strain, is capable of suppressing inflammation reducing fibrosis vivo. To ascertain the mechanism driving this activity determine if it specific we compared porcine tropic strain...
Toll-like receptors (TLRs) activate distinct, yet overlapping sets of signaling molecules, leading to inflammatory responses pathogens. Toll/interleukin-1 receptor (TIR) domains, present in all TLRs and TLR adapters, mediate protein interactions downstream activated TLRs. A peptide library derived from TLR2 TIR was screened for inhibition signaling. Cell-permeable peptides the D helix segment immediately N-terminal domain potently inhibited TLR2-mediated cytokine production. The D-helix...
Significance This study sheds light on the mechanisms of Toll-like receptor 4 (TLR4) signaling complex assembly. Particularly, interaction site that mediates Toll/IL-1R resistance (TIR) domain–containing adapter-inducing IFN-β (TRIF) recruitment to TLR4 is identified within second helical region TRIF TIR domain. finding significant because “a mimic” this potently inhibits in cells by a competitive mechanism and decreases LPS-induced mortality mice more than 80%.
Toll-like receptor 4 (TLR4) recognition of lipopolysaccharide triggers signalosome assembly among TLR4, sorting (e.g. MyD88 adapter-like (Mal)) and signaling MyD88) adapters, initiating recruitment activation kinases, transcription factors, production inflammatory mediators. In this study we examined whether tyrosine phosphorylation Mal regulates its interactions with MyD88, interleukin-1 (IL-1) receptor-associated kinase (IRAK)-2, tumor necrosis factor (TRAF)-6 is important for signaling....
Abstract The homeostasis of CD4 + CD25 regulatory T cells (Tregs) depends on the cytokine interleukin (IL)‐2. As IL‐21 shares sequence homology with IL‐2 and receptors contain a γ‐chain common to IL‐2, we hypothesized that could also affect Tregs. We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), an animal model relapsing‐remitting human multiple sclerosis. show blockade SJL/J mice before after induction EAE enhances influx inflammatory into central nervous system...
Abstract Toll/IL-1R (TIR) domain-containing adapter-inducing IFN-β (TRIF)–related adapter molecule (TRAM) serves as a bridging that enables recruitment of TRIF to activated TLR4 and thereby mediates the induction TRIF-dependent cytokines. A library cell-permeating decoy peptides derived from TRAM TIR domain has been screened for ability individual inhibit signaling in primary murine macrophages. Peptides BB loop (TM4) C helix (TM6) inhibited LPS-induced activation MyD88-dependent cytokines,...
Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre-/- × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting reduced Tregs dendritic cells, decreased high endothelial venules, impaired conduit system,...
Abstract Lymphotoxin-beta receptor (LTβR) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent transendothelial migration (TEM). The function of individual pathways for different subsets is currently unknown. Here, we show that LTβR signals predominantly via the constitutive and ligand-driven non-classical NIK pathway. Targeting LTβR-NIK by an LTβR-derived decoy peptide (nciLT) suppresses production chemokines CCL21 CXCL12, enhances expression classical NFκB-driven...
Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4+ T but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted decreased protein LN cortical ridge (CR) and around high endothelial venules (HEVs). depletion affected structure with increased HEVs, upregulated chemokines, cell adhesion molecules, led to greater numbers Tregs zone. Mouse human...
Regulatory T cell (Treg) lymphatic migration is required for resolving inflammation and prolonging allograft survival. Focusing on Treg interactions with endothelial cells (LECs), we dissect mechanisms functional consequences of transendothelial (TEM). Using three genetic mouse models pancreatic islet transplantation, show that lymphotoxin (LT) αβ LEC LTβ receptor (LTβR) signaling are efficient suppressive function to prolong Inhibition LT increases conversion Foxp3loCD25lo exTregs. In a...