
Bernd H ZinselmeyerWashington University in St. Louis | WUSTL , Wash U · Department of Pathology and Immunology
Bernd H Zinselmeyer
Doctor of Philosophy
About
205
Publications
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Introduction
My skills and interests are broad: botany, mycology, biochemistry, molecular and cell biology, applied skills in chemical and physiochemical techniques (e.g. structural NMR and photon-correlation spectroscopy). In my PhD project I designed, synthesized and characterized compounds for gene delivery. Earning my PhD in pharmaceutical science has inspired me conducting research relevant to clinical medicine. The focus of my work is intravital 2P- imaging of cells of the immune system and the CNS.
Additional affiliations
January 2016 - present
June 2013 - December 2015
July 2003 - June 2006
Publications
Publications (205)
More than 80% of ovarian cancer (OC) cases have metastasized to the peritoneal cavity at diagnosis. The five-year survival rate for these patients is 25%. Within the peritoneal cavity, the most common and early site of metastasis is the omentum, a well-vascularized, specialized adipose tissue that arises off the greater curvature of the stomach. Be...
The pore-forming S. aureus α-toxin (Hla) contributes to virulence and disease pathogenesis. While high concentrations of toxin induce cell death, neutrophils exhibit relative resistance to lysis, suggesting that the action of Hla may not be solely conferred by lytic susceptibility. Using intravital microscopy, we observed that Hla disrupts neutroph...
Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, t...
The central nervous system (CNS) antigen-presenting cell (APC) that primes anti-tumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDC localize to the choroid plexus and dura. Thus, whether the cDC1 play a...
Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, t...
Recently, studies have emerged suggesting that the skin plays a role as major Na⁺ reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. We investigated whether there were electrolyte gradients in skin and where Na⁺ could be stored to be inactivated from a fluid balance viewpoint. Na⁺ accumulation was induced in rats b...
Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn’s disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔAR...
Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/− and LYVE1lo/− MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial...
Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without...
The central nervous system (CNS) antigen presenting cell (APC) which primes anti-tumor CD8 ⁺ T cell responses remains undefined. Elsewhere, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain cDC1 are rare; cDC localize to choroid plexus and dura. Using preclinical glioblastoma models and cDC1-deficient mice, we...
The concept that impaired lymphatic flow during the progression of Crohn’s disease, a major form of inflammatory bowel disease, emerged decades ago, but remains unresolved. In Crohn’s disease, tertiary lymphoid organs (TLOs) are associated with collecting lymphatic vessels (CLVs) of the mesentery that govern lymph outflow from the intestine. Whethe...
Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabol- ically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring...
Pioneer reports of Crohn’s disease (CD) suggested that impaired lymphatic flow might drive its pathogenesis but remains unsettled. Nodules of tertiary lymphoid organs (TLO) are found in association with collecting lymphatic vessels (CLVs) of the mesentery that normally conducts lymph outflow from the intestine. Whether TLOs affect lymph transport i...
The antigen presenting cell that primes T cells in the central nervous system (CNS) remains unknown. Outside the CNS, the conventional dendritic cell 1 (cDC1) subset presents antigen to and primes CD8 T cells. However, the steady-state CNS parenchyma is relatively devoid of all dendritic cell subsets, including cDC1. cDC1 are required for anti-tumo...
Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stag...
Key points
Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the KATP channel activator pinacidil. KATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional KATP channels as verified by electrophysiological techniques.
Global de...
Current understanding of Crohn’s disease (CD) is that hereditary factors render the mucosal surface susceptible by either deregulated interactions between the bacterial flora and surface epithelial cells or an overwhelming host immune response. Given that lymph flow is essential for leukocyte trafficking and lipid absorption, understanding the effe...
Bacteria express multiple diverse capsular polysaccharides (CPSs) for protection against environmental and host factors, including the host immune system. Using a mouse TCR transgenic CD4+ T cell, BθOM, that is specific for B. thetaiotaomicron and a complete set of single CPS-expressing B. thetaiotaomicron strains, we ask whether CPSs can modify th...
Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-k...
Video 1.
Intravital imaging of peritoneal macrophages through the intact abdominal wall. An intravital preparation for two-photon imaging through the intact abdominal is schematically depicted. Bhlhe40GFP mice were used to visualize peritoneal macrophages, as LPMs were high expressers of GFP in this mouse model, and B cells, another numerous leukoc...
Figure S1. Coagulation and adhesion additively cooperate to account for the MDR in response to inflammation. (A and B) Neutrophil numbers (A) and LPM numbers (B) in the peritoneal lavage at 3 h after zymosan injection with or without neutrophil depletion using an anti-Ly6G monoclonal antibody (1A8). (C) Neutrophil numbers in the peritoneal lavage a...
Video 2.
Intravital imaging of a clot after removal from a mouse 3 h after injection of GFP–E. coli. Clots were removed at 3 h after E. coli was injected i.p. and placed in a chamber for two-photon microscopy to be assessed ex vivo. Video 2 shows E. coli in green; Lyz2Cre;R26LSL-Tdtomato mice were used to reveal myeloid cells in clots that appear t...
We have been examining how beta cells communicate their antigens to the innate immune system, in the context of the diabetic autoimmunity. Beta cells release peptides derived from the insulin granules intermittently into the blood following challenges with glucose. Most of the peptides derive from crinosomes, degradative vesicles that result from t...
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on ski...
Characterization of Crohn’s disease (CD) includes susceptible mucosal surfaces via abnormal intestinal permeability caused by either deregulated interactions between the bacterial flora and surface epithelial cells or an overwhelming host immune response. However, historical and recent studies demonstrate lymphatic vessel obstruction and lymphangit...
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on ski...
With the beginning of the new millennium intravital multiphoton imaging of the immune system has become a necessary tool for understanding cellular behavior in steady state and models of disease, in vivo . The first studies visualized dynamics of antigen presenting cells and T‐cells. Followed by development of fluorescent reporter mice that allowed...
Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential f...
Objective—Macrophages play important roles in the pathogenesis of atherosclerosis, but their dynamics within
plaques remain obscure. We aimed to quantify macrophage positional dynamics within progressing and regressing
atherosclerotic plaques.
Approach and Results—In a stable intravital preparation, large asymmetrical foamy macrophages in the intim...
Aims/hypothesis:
We studied here the interactions between the resident macrophages of pancreatic islets with beta cells and the blood vasculature. We also examined the immunological consequences of such interactions.
Methods:
Islets were isolated from C57BL/6 mice expressing CX3C motif chemokine receptor 1-green fluorescent protein (CX3CR-GFP) a...
Macrophages reside in the vascular intima of the aorta in plaque prone regions. Intima macrophages were found to be ‘tissue resident’, possessing the ability to self-renew independent of circulating monocytes and having a unique dependence on Csf1 and Flt3 pathways for development. Lineage tracing and depletion experiments showed these cells were r...
Tissue resident macrophages are found at birth in the islets of Langerhans of all strains of mice examined. To examine the macrophage’s role in islet homeostasis and diabetogenesis, we depleted the cells using a monoclonal antibody against the CSF-1 receptor. Depletion of islet macrophages in the C57BL/6 mouse strain for 2–6 weeks did not affect mu...
Using RNAseq, we examined the transcriptome of endocrine macrophage in the islets of Langerhans in NOD (non-obese diabetic) and in two non-diabetic controls: NOD.Rag1−/− and B6.g7. The NOD mice spontaneously develop diabetes at 20–24 weeks of age. By gene expression analysis we found that at 3 weeks of age the macrophages from all 3 strains of mice...
Relatively little is known with regard to CD4 T cell memory formation and metabolism, in part because CD4 T cell numbers remain low during a recall infection. Further, the contribution of self-peptide-MHC signaling (during both thymic T cell development and peripheral maintenance) to metabolic programming, if any, remains unknown. To address these...
Recognition of insulin is essential for initiating autoimmune diabetes in the non-obese diabetic (NOD) mice; however, how this autoantigen is presented to pathogenic T cells remains unclear. In patients with type 1 diabetes, insulin autoantibodies (IAAs) are the earliest sign of disease. In NOD mice IAAs are detected before immune infiltration in i...
Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation o...
Dendritic cells (DCs) are thought to form a dendritic network across barrier surfaces and throughout organs, including the kidney, to perform an important sentinel function. However, previous studies of DC function used markers, such as CD11c or CX3CR1, that are not unique to DCs. Here, we evaluated the role of DCs in renal inflammation using a CD1...
Significance
Our studies indicate that the resident macrophages of the pancreatic islets of Langerhans have a seminal role in the initiation and progression of autoimmune diabetes in NOD mice. In this study, islet macrophages were depleted by administration of a monoclonal antibody to the CSF-1 receptor. Macrophage depletion, either at the start of...
Rationale: Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective due to UCP1-dependent thermogenesis.
Objective: We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in...
HDL is cardioprotective, but plasma HDL levels do not necessarily predict cardiovascular outcomes. The major HDL-associated protein apoA-I picks up its cholesterol from cells within extravascular compartments to return it to plasma and then bile. Yet, tools are lacking to quantify the important step of HDL transit through extravascular spaces. Here...
Atherosclerosis is an underlying cause of cardiovascular disease and a leading cause of mortality worldwide. Macrophage accumulation in atherosclerotic plaque, their uptake of cholesterol, and subsequent local death drive disease progression. Lipid-laden plaque macrophages are thought to be exclusively derived from blood monocyte progenitors that a...
Atherosclerosis is the leading cause of heart disease, which is the largest contributor to deaths across the world. This disease involves the development of inflammation and plaque formation within the lumen of mid- and large-sized arteries following cholesterol-enriched diet. Our current study uses intravital two photon imaging to examine the init...