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Publications (93)
Allergic conditions are associated with canonical and non-canonical activation of the complement system leading to the release of several bioactive mediators with inflammatory and immunoregulatory properties that regulate the immune response in response to allergens during the sensitization and/or the effector phase of allergic diseases. Further, i...
Background:
Pulmonary eosinophils comprise at least two distinct populations of resident eosinophils (rEOS) and inflammatory eosinophils (iEOS), the latter recruited in response to pulmonary inflammation. Here, we determined the impact of complement activation on rEOS and iEOS trafficking and function in two models of pulmonary inflammation.
Meth...
Microbial maturation disrupted by early life dysbiosis has been linked with increased asthma risk and severity, however the immunological mechanisms underpinning this connection are poorly understood. We sought to understand how delaying microbial maturation drives worsened asthma outcomes later in life and its long-term durability. Drinking water...
Asthma is one of the most common chronic diseases. Mucus overproduction is consistently linked to asthma morbidity and mortality. Despite the knowledge of the importance of mucus, little data exists on how mucus is transported in asthma and the immediate effects of therapeutic intervention. We therefore used microscopic optical coherence tomography...
Changes in microbiome (dysbiosis) contribute to severity of allergic asthma. Preexisting epidemiological studies in humans correlate perinatal dysbiosis with increased long-term asthma severity. However, these studies cannot discriminate between prenatal and postnatal effects of dysbiosis and suffer from a high variability of dysbiotic causes rangi...
Background
Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).
Objective
To delineate the degradation of COL4A3 in allergic airway inflammation and evaluat...
Food allergies are common, costly and potentially life-threatening disorders. They are driven by Th2, but inhibited by Th1 reactions. There is also evidence indicating that IL-2 agonist treatment inhibits allergic sensitization through expansion of regulatory T cells. Here, we tested the impact of an IL-2 agonist in a novel model for food allergy t...
Allergic asthma is a chronical pulmonary disease with high prevalence. It manifests as a maladaptive immune response to common airborne allergens and is characterized by airway hyperresponsiveness, eosinophilia, type 2 cytokine-associated inflammation, and mucus overproduction. Alveolar macrophages (AMs), although contributing to lung homeostasis a...
The anaphylatoxins (AT) C3a and C5a are effector molecules of C3 and C5 exerting multiple biologic functions through binding and activation of their cognate G protein−coupled receptors. C3a interacts with the C3a receptor (C3aR), whereas C5a and its primary degradation product C5a‐desArg engage C5aR1 and C5aR2. In the past, analysis of AT expressio...
Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b+ conventional dendritic cells (cDCs) in the context of house-dust-mite (HDM) exposure. BALB/c mice were intratr...
Background:
A close asssociation between obesity and asthma has been described. The nature of this association remains elusive, especially with respect to allergic asthma. Controversial findings exist regarding the impact short-term high fat diet (HFD) feeding on the development of allergic asthma.
Objective:
To delineate the impact of short-ter...
The division of labor between pulmonary phagocytic subsets [macrophage/monocyte and dendritic cell (DC) subpopulations] has been described at the functional level. However, whether these lung phagocytes also display unique spatial distribution remains unclear. Here, to analyze cellular distribution in lung compartments and contacts between phagocyt...
C5a regulates the development of maladaptive immune responses in allergic asthma mainly through the activation of C5a receptor 1 (C5aR1). Yet, the cell types and the mechanisms underlying this regulation are ill-defined. Recently, we described increased C5aR1 expression in lung tissue eosinophils but decreased expression in airway and pulmonary mac...
The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed pictur...
C3a exerts multiple biologic functions through activation of its cognate C3a receptor. C3(-/-) and C3aR(-/-) mice have been instrumental in defining important roles of the C3a/C3aR axis in the regulation of acute and chronic inflammatory diseases, including ischemia/reperfusion injury, allergic asthma, autoimmune nephritis, and rheumatoid arthritis...
The anaphylatoxins (AT) C3a and C5a play important roles as mediators of inflammation. Further, they regulate and control multiple innate and adaptive immune responses through binding and activation of their cognate G protein-coupled receptors, i.e. C3a receptor (C3aR), C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2), although the latter lacks im...
Eosinophils are considered a homogenous cell population, contributing to the allergic asthma phenotype by promoting mucus hypersecretion and airway hyperresponsiveness. Here, we identified a previously unrecognized vacuolated CD11cdim eosinophilic population (vEOS) which accmulates exclusively in the lung tissue and in mediastinal lymph nodes but n...
The anaphylatoxin C3a exerts its biologic functions through the activation of its cognate G-protein-coupled receptor C3a receptor (C3aR). C3aR mRNA expression has been described both in human and mouse lungs. However, no systematic analysis of C3aR expression at steady state and under pro-inflammatory conditions in the different pulmonary cell subs...
C5a drives airway constriction and inflammation during the effector phase of allergic asthma, mainly through the activation of C5a receptor 1 (C5aR1). Yet, C5aR1 expression on myeloid and lymphoid cells during the allergic effector phase is ill-defined. Recently, we generated and characterized a floxed green fluorescent protein (GFP)-C5aR1 knock-in...
Evaluation of C5aR1 expression in neutrophils and CD103+ cDCs.
(A) Histograms showing the expression levels of GFP, used as surrogate marker for C5aR1 expression, in lung neutrophils in PBS-treated or OVA-challenged GFP-C5aR1flox/flox animals. The corresponding graph on the right shows the mean fluorescence intensity (MFI) of the GFP signal in neut...
OVA-induced experimental allergic asthma model.
WT C5aR1+/+ and GFP-C5aR1flox/flox reporter mice were immunized twice i.p. with either PBS/Alum or OVA/Alum at days 0 and 7. Airways were challenged by i.t. administration of 50 μl PBS in the PBS control group or 1.5% OVA solution in PBS in the OVA-immunization group on days 14, 16, 18 and 20. On day...
Surface expression of C5aR1.
Cells isolated from WT and C5aR1-/- mice under steady state conditions were stained for C5aR1 (CD88) as described in material and methods. (A/B) C5aR1 surface staining on eosinophils and tissue-associated alveolar macrophages (A) as well as different DC subsets (B) as described in Fig 2D. Data are representative of two...
Allergic asthma is a disease of the airways driven by maladaptive T helper 2 (Th2) and Th17 immune response against harmless, airborne substances. The hallmarks of this disease are airway hyperresponsiveness (AHR), eosinophilic and neutrophilic airway inflammation and mucus overproduction. Distinct dendric cell (DC) subsets together with airway epi...
The activation of the complement system by canonical and non-canonical mechanisms results in the generation of multiple C3 and C5 cleavage fragments including anaphylatoxins C3a and C5a as well as opsonizing C3b/iC3b. It is now well appreciated that anaphylatoxins not only act as pro-inflammatory mediators but as immunoregulatory molecules that con...
Allergic asthma is a chronic inflammatory disease of the airways that is driven by maladaptive T helper 2 (Th2) and Th17 immune responses against harmless, airborne substances. Pulmonary phagocytes represent the first line of defense in the lung where they constantly sense the local environment for potential threats. They comprise two distinct cell...
Many of the biological properties of C5a are mediated through activation of its receptor (C5aR1), the expression of which has been demonstrated convincingly on myeloid cells, such as neutrophils, monocytes, and macrophages. In contrast, conflicting results exist regarding C5aR1 expression in dendritic cells (DCs) and lymphoid lineage cells. In this...
Conventional dendritic cells (cDC) are necessary and sufficient to drive mixed maladaptive Th2/Th17 immune responses toward aeroallergens in experimental allergy models. Previous studies suggest that the anaphylatoxin C3a promotes, whereas C5a protects from the development of maladaptive immunity during allergen sensitization. However, only limited...
C5a is a powerful proinflammatory and immunomodulatory mediator as evidenced by its involvement in infectious, allergic, and autoimmune diseases as well as in cancer. C5a exerts most of its biologic functions through binding and activation of the G protein-coupled C5a receptor (C5aR). C5aR activation promotes complex signaling pathways eventually r...
Allergic asthma is a chronic disease of the airways in which maladaptive Th2 and Th17 immune responses drive airway hyperresponsiveness (AHR), eosinophilic and neutrophilic airway inflammation and mucus overproduction. Airway epithelial and pulmonary vascular endothelial cells in concert with different resident and monocyte-derived dendritic cells...
In the present study, monocyte-derived human macrophages were differentiated from buffy coats. Naïve CD4(+) T-cells enriched from peripheral blood mononuclear cells using anti-CD4 magnetic beads and the autoMACS separation system were polarized under T-helper 17 (Th17)-promoting conditions for 6 days to get Th17 cells. The frequency of Th17 cell di...
The pathways underlying dendritic cell (DC) activation in allergic asthma are incompletely understood. Here we demonstrate that adoptive transfer of ovalbumin-pulsed wild-type (wt) but not of C5a receptor-deficient (C5aR(-/-)) bone marrow (BM)-derived DCs (BMDCs) induced mixed T helper type 2 (Th2)/Th17 maladaptive immunity, associated with severe...
Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T- and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions re...
Complement, NKT, and NK cells play critical roles in the first line defense against pathogens. Functional roles for both C5a receptors, that is, complement receptor C5a (C5aR) and C5a receptor-like 2 (C5L2), in sepsis have been demonstrated. However, the role of C5a in innate lymphocyte activation during sepsis remains elusive. In this article, we...
To identify proteins that interact with the C-terminal fragment of annexin A2 (A2IC), generated by plasmin cleavage of the plasmin receptor, a heterotetramer (AA2t) containing annexin A2.
The gene that encodes the A2IC fragment was obtained from PCR-amplified cDNA isolated from human monocytes, and was ligated into the pBTM116 vector using a DNA li...
TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how...
Allergic rhinitis and asthma are common chronic inflammatory diseases of the nasal mucus membranes and the upper airways with a high prevalence in Western countries. In addition to maladaptive T-helper type 2 (Th2) immunity, Th17 cells can drive the inflammatory responses in both diseases. Several reports have shown that the complement system is ac...
The complement fragment C5a plays dual roles in the development of experimental allergic asthma. It protects from pulmonary allergy by a regulatory effect on dendritic cells during allergen sensitization, but is proallergic during the effector phase. C5a can bind to two distinct receptors (i.e., C5a receptor and C5a receptor-like 2 [C5L2]). The fun...
Plasmin is recognized as a potent signaling molecule in particular human monocytes, inducing a pro-inflammatory response. Recently, the annexin A2 heterotetramer, a plasmin receptor, was described at the surface of the human monocytes. Plasmin is initiating a signaling in monocytes by cleavage of the annexin A2 subunit of the receptor and the appar...
Human cytomegalovirus (HCMV) establishes a life-long persistent infection. HCMV infection could be associated with chronic
inflammatory diseases, such as cardiovascular disease and atherosclerosis. Here we observed that in HCMV (AD-169) pre-exposed
human umbilical vein endothelial cells (HUVEC), thrombin-induced expression of IL-1α and M-CSF is mar...
Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to...
Protease-activated receptors (PARs) are a family of G protein-coupled receptors that are activated by serine protease-mediated proteolytic cleavage of their extracellular domain. We have previously characterized the expression and function of PARs in human monocytes and macrophages, yet information about PARs in dendritic cells (DC) is scarce. Mono...
CX3CL1 (fractalkine, neurotactin) is the sole CX3C chemokine. It induces monocyte locomotion in its cleaved form, but in its membrane-anchored form, it also acts as an adhesion molecule. The expression of CX3CL1 is up-regulated in endothelial cells by proinflammatory cytokines such as IL-1 or TNF-alpha. Here, we studied the effect of the serine pro...
Monocyte‐derived immature dendritic cells (DC) do not express protease‐activated receptors (PARs). However, upon maturation with LPS, but not with TNF‐α or CD40L, DC express PAR1 and PAR3, but not PAR2 or PAR4. Stimulation of matured DC with thrombin, PAR1‐ or PAR3‐activating peptides elicits actin polymerization and concentration‐dependent chemota...
Fibrinolytic activity is upregulated in atherosclerotic lesions, yet little is known about the role of plasmin in macrophage function. We postulated a direct effect of plasmin on human monocyte-derived macrophages.
Plasmin activates macrophages via the annexin A2 heterotetramer composed of annexin A2 and S100A10 with subsequent stimulation of Janus...
We have previously demonstrated that plasmin acts as potent proinflammatory activator of human peripheral monocytes leading to activation of protein kinase cascades and a number of transcription factors. An uncompromised proteolytic activity was essential for the plasmin-mediated monocyte activation pointing to the necessity of a proteolytic activa...
We have previously demonstrated that plasmin acts as a potent proinflammatory activator of human peripheral monocytes. Here we identify the annexin A2 heterotetramer, composed of annexin A2 and S100A10, as a receptor for the plasmin-induced signaling in human monocytes. Monocytes express the annexin A2 heterotetramer on the cell surface as shown by...