Alex F de Vos

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (103)564.31 Total impact

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    ABSTRACT: The receptor for advanced glycation endproducts (RAGE) has been implicated in the regulation of skin inflammation. We here sought to study the role of RAGE in host defense during skin infection caused by Staphylococcus (S.) aureus, the most common pathogen in this condition. Wild-type (Wt) and RAGE deficient (rage(-/-)) mice were infected subcutaneously with S. aureus and bacterial loads and local inflammation were quantified at regular intervals up to 8 days after infection. While bacterial burdens were similar in both mouse strains at the primary site of infection, rage(-/-) mice had lower bacterial counts in lungs and liver. Skin cytokine and chemokine levels did not differ between groups. In accordance with the skin model, direct intravenous infection with S. aureus was associated with lower bacterial loads in lungs and liver of rage(-/-) mice. Together these data suggest that RAGE does not impact local host defense during S. aureus skin infection, but facilitates bacterial growth at distant body sites. Copyright © 2015. Published by Elsevier Masson SAS.
    Microbes and Infection 06/2015; 5. DOI:10.1016/j.micinf.2015.06.002 · 2.73 Impact Factor
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    ABSTRACT: Klebsiella pneumoniae is an important cause of Gram-negative pneumonia and sepsis. Mice deficient for TIR-domain-containing adaptor-inducing interferon-β (TRIF) demonstrate enhanced bacterial growth and dissemination during Klebsiella pneumonia. We show here that the impaired antibacterial defense of TRIF mutant mice is associated with absent interferon (IFN)-γ production in the lungs. IFN-γ production by splenocytes in response to K. pneumoniae in vitro was critically dependent on Toll-like receptor 4 (TLR4), the common TLR adaptor myeloid differentiation primary response gene (MyD88) and TRIF. Reconstitution of TRIF mutant mice with recombinant IFN-γ via the airways reduced bacterial loads in lungs and distant body sites to levels measured in wild-type mice, and partially restored pulmonary cytokine levels. The IFN-γ-induced, improved, enhanced antibacterial response in TRIF mutant mice occurred at the expense of increased hepatocellular injury. These data indicate that TRIF mediates antibacterial defense during Gram-negative pneumonia, at least in part, by inducing IFN-γ at the primary site of infection. © 2015 S. Karger AG, Basel.
    Journal of Innate Immunity 06/2015; DOI:10.1159/000430913 · 4.56 Impact Factor
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    ABSTRACT: Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. Granzymes (gzms) are proteases mainly found in cytotoxic lymphocytes, but also extracellularly. While the role of gzms in target cell death has been widely characterized, considerable evidence points towards broader roles related to infectious and inflammatory responses. To investigate the expression of the gzms in TB, intracellular gzms A, B and K were measured by flow cytometry in lymphocyte populations from peripheral blood mononuclear cells from 18 TB patients and 12 healthy donors from Bangladesh, and extracellular levels of gzmA and B were measured in serum from 58 TB patients and 31 healthy controls. TB patients showed increased expression of gzmA in CD8(+) T, CD4(+) T and CD56(+) T, but not NK, cells, and of gzmB in CD8(+) T cells, when compared to controls. GzmK expression was not altered in TB patients in any lymphocyte subset. The extracellular levels of gzmA and, to a lesser extent, of gzmB, were increased in TB patients, but did not correlate with intracellular gzm expression in lymphocyte subsets. Our results reveal enhanced intra- and extracellular expression of gzmA and B in patients with pulmonary TB, suggesting that gzms are part of the host response to tuberculosis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Tuberculosis (Edinburgh, Scotland) 06/2015; DOI:10.1016/ · 3.50 Impact Factor
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    ABSTRACT: Triggering Receptor Expressed on Myeloid cells (TREM)-1 and -2 can affect Toll-like receptor mediated activation of immune cells. Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Here we studied the role of TREM-1/3 and TREM-2 in the host response during Klebsiella pneumonia. Macrophages lacking either TREM-1/3 or TREM-2 were tested for their responsiveness towards K. pneumoniae as well as their capacity to internalize this pathogen in vitro. TREM-1/3 and TREM-2 deficient mice were infected with K. pneumoniae via the airways and their responses were compared with those in wild type mice. TREM-1/3 deficient macrophages produced lower cytokine levels upon exposure to K. pneumoniae, while on the opposite TREM-2 deficient macrophages released higher cytokine concentrations. TREM-2 deficient, but not TREM-1/3 deficient, macrophages showed a reduced capacity to phagocytose K. pneumoniae. TREM-1/3 deficient mice showed an impaired host defense during Klebsiella pneumonia, as reflected by worsened survival and increased bacterial growth and dissemination. In contrast, TREM-2 deficiency did not impact on disease outcome. Although TREM-1/3 and TREM-2 influence macrophage responsiveness to K. pneumoniae in vitro, only TREM-1/3 contribute to the host response during Klebsiella pneumonia in vivo, serving a protective role.
    American Journal of Respiratory Cell and Molecular Biology 04/2015; DOI:10.1165/rcmb.2014-0485OC · 4.11 Impact Factor
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    ABSTRACT: Typhoid fever, caused by the Gram-negative bacterium Salmonella enterica serovar Typhi, is a major cause of community-acquired bacteremia and death worldwide. S100A8 (MRP8) and S100A9 (MRP14) form bioactive antimicrobial heterodimers (calprotectin) that can activate Toll-like receptor 4, promoting lethal, endotoxin-induced shock and multi-organ failure. We aimed to characterize the expression and function of S100A8/A9 in patients with typhoid fever and in a murine invasive Salmonella model. S100A8/A9 protein levels were determined in acute phase plasma or feces from 28 Bangladeshi patients, and convalescent phase plasma from 60 Indonesian patients with blood culture or PCR-confirmed typhoid fever, and compared to 98 healthy control subjects. To functionally characterize the role of S100A8/A9, we challenged wildtype (WT) and S100A9-/- mice with S. Typhimurium and determined bacterial loads and inflammation 2- and 5- days post infection. We further assessed the antimicrobial function of recombinant S100A8/A9 on S. Typhimurium and S. Typhi replication in vitro. Typhoid fever patients demonstrated a marked increase of S100A8/A9 in acute phase plasma and feces and this increases correlated with duration of fever prior to admission. S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. WT mice inoculated with S. Typhimurium showed increased levels of S100A8/A9 in both the liver and the systemic compartment but S100A9-/- mice were indistinguishable from WT mice with respect to bacterial growth, survival, and inflammatory responses, as determined by cytokine release, histopathology and organ injury. S100A8/A9 is markedly elevated in human typhoid, correlates with duration of fever prior to admission and directly inhibits the growth of S. Typhimurium and S. Typhi in vitro. Despite elevated levels in the murine invasive Salmonella model, S100A8/A9 does not contribute to an effective host response against S. Typhimurium in mice.
    PLoS Neglected Tropical Diseases 04/2015; 9(4):e0003663. DOI:10.1371/journal.pntd.0003663 · 4.49 Impact Factor
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    ABSTRACT: Staphylococcus aureus has evolved as an important cause of pneumonia in both hospital and community settings. Staphylococcal lung infection can lead to overwhelming pulmonary inflammation. During infection, neutrophils release complexes of myeloid-related protein (MRP)8 and MRP14 (MRP8/14). MRP8/14 has been shown to exert pro-inflammatory and chemotactic activity, and to assist in the killing of S. aureus. In the current study we sought to determine the role of MRP8/14 in the host response during S. aureus pneumonia. Pneumonia was induced in wildtype and MRP14-deficient mice (mice unable to form MRP8/14) by intranasal inoculation of 1×10(7) CFU of S. aureus USA300. Mice were sacrificed at 6, 24, 48 or 72 h after infection for analyses. S. aureus pneumonia was associated with a strong rise in MRP8/14 in bronchoalveolar lavage fluid and lung tissue. Surprisingly, MRP14 deficiency had a limited effect on bacterial clearance and was associated with increased cytokine levels in bronchoalveolar lavage fluid and aggravated lung histopathology. MRP14 deficiency in addition was associated with a diminished transmigration of neutrophils into bronchoalveolar lavage fluid at late time-points after infection together with reduced release of nucleosomes. MRP8/14 serves in an unexpected protective role for the lung in staphylococcal pneumonia. Copyright ©ERS 2015.
    European Respiratory Journal 03/2015; DOI:10.1183/09031936.00183814 · 7.13 Impact Factor
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    ABSTRACT: Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. Toll-like-receptors (TLRs) are important for the recognition of the causative agent Mycobacterium tuberculosis. Negative regulation of TLRs is necessary to control deleterious inflammatory damage, but could provide a means of immune evasion by M. tuberculosis as well. To obtain insight in the extent of expression of inhibitory regulators of immunity in patients with active TB, peripheral-blood-mononuclear-cells (PBMCs) and plasma were obtained from 54 TB patients and 29 healthy blood donors from Chittagong, Bangladesh. Bilateral alveolar macrophages were obtained from an infected versus a contralateral normal lung segment of 9 patients. Statistical analyses were performed using Mann–Whitney U and Wilcoxon matched pairs testing. Correlations were calculated using the Spearman rho test. PBMCs harvested from TB patients demonstrated increased mRNA expression of IL-1-receptor-associated-kinase-M, suppressor-of-cytokine-signalling-3 and Toll-interacting-protein. Flow cytometry revealed enhanced expression of IL-1-receptor-like-1 (ST2) on lymphocytes. Plasma soluble ST2 was elevated in patients with TB and correlated with established TB biomarkers, most strongly with soluble interleukin-2 receptor subunit α and interleukin-8. Alveolar macrophage mRNA expression of negative TLR regulators did not differ between the infected and contralateral lung side. These results show enhanced expression of distinct negative regulators of innate immunity in PBMCs of patients with TB and identify plasma soluble ST2 as a potential novel biomarker for TB disease activity.
    BMC Infectious Diseases 02/2015; 15(1). DOI:10.1186/s12879-015-0833-z · 2.61 Impact Factor
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    ABSTRACT: Toll-like receptors (TLR) and the downstream adaptor protein MyD88 are considered crucial for protective immunity during bacterial infections. Streptococcus (S.) pneumoniae is a human respiratory pathogen and a large majority of clinical pneumococcal isolates expresses an external polysaccharide capsule. We here sought to determine the role of pneumococcal capsule in MyD88-mediated antibacterial defense during S. pneumonia pneumonia. Wild type (WT) and Myd88-/- mice were inoculated intranasally with serotype 2 S. pneumoniae D39 or with an isogenic capsule locus deletion mutant (D39∆cps), and analysed for bacterial outgrowth and inflammatory responses in the lung. As compared to WT mice, Myd88-/- mice infected with D39 demonstrated a modestly impaired bacterial clearance accompanied by decreased inflammatory responses in the lung. Strikingly, while WT mice rapidly cleared D39∆cps, Myd88-/- mice showed 105-fold higher bacterial burdens in their lungs and dissemination to blood 24 hours after infection. These data suggest that the pneumococcal capsule impairs recognition of TLR ligands expressed by S. pneumoniae and thereby partially impedes MyD88-mediated antibacterial defense.
    PLoS ONE 02/2015; 10(2):e0118181. DOI:10.1371/journal.pone.0118181 · 3.23 Impact Factor
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    ABSTRACT: Objectives: Streptococcus pneumoniae is the most common causative organism in community-acquired pneumonia responsible for millions of deaths every year. DNAX-activating protein of 12 kDa is an adaptor molecule for different myeloid expressed receptors involved in innate immunity. Design: Animal study. Setting: University research laboratory. Subjects: DNAX-activating protein of 12 kDa–deficient (dap12–/–) and wild-type mice. Interventions: Mice were intranasally infected with S. pneumoniae. In addition, ex vivo responsiveness of alveolar macrophages was examined. Measurements and Main Results: dap12–/– alveolar macrophages released more tumor necrosis factor-α upon stimulation with S. pneumoniae and displayed increased phagocytosis of this pathogen compared with wild-type cells. After infection with S. pneumoniae via the airways, dap12–/– mice demonstrated reduced bacterial outgrowth in the lungs together with delayed dissemination to distant body sites relative to wild-type mice. This favorable response in dap12–/– mice was accompanied by reduced lung inflammation and an improved survival. Conclusions: These data suggest that DNAX-activating protein of 12 kDa impairs host defense during pneumococcal pneumonia at the primary site of infection at least in part by inhibiting phagocytosis by alveolar macrophages.
    Critical Care Medicine 12/2014; 42(12):e783-90. DOI:10.1097/CCM.0000000000000686 · 6.15 Impact Factor
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    ABSTRACT: Klebsiella pneumoniae is an important cause of sepsis. The common Toll-like receptor adapter myeloid differentiation primary response gene (MyD)88 is crucial for host defense against Klebsiella. Here we investigated the role of MyD88 in myeloid and endothelial cells during Klebsiella pneumosepsis. Mice deficient for MyD88 in myeloid (LysM-Myd88-/-) and myeloid plus endothelial (Tie2-Myd88-/-) cells showed enhanced lethality and bacterial growth. Tie2-Myd88-/- mice reconstituted with control bone marrow, representing mice with a selective MyD88 deficiency in endothelial cells, showed an unremarkable antibacterial defense. Myeloid or endothelial cell MyD88 deficiency did not impact on lung pathology or distant organ injury during late stage sepsis, while LysM-Myd88-/- mice demonstrated a strongly attenuated inflammatory response in the airways early after infection. These data suggest that myeloid but not endothelial MyD88 is important for host defense during gram-negative pneumonia derived sepsis.
    PLoS Pathogens 09/2014; 10(9):e1004368. DOI:10.1371/journal.ppat.1004368 · 8.14 Impact Factor
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    ABSTRACT: Background Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia. Methods MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro. Results CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14. Conclusions In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.
    Thorax 09/2014; 69(11). DOI:10.1136/thoraxjnl-2014-205668 · 8.56 Impact Factor
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    ABSTRACT: Streptococcus (S.) pneumoniae is a common gram-positive pathogen in community-acquired pneumonia and sepsis. Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is a receptor on phagocytes known to amplify inflammatory responses. Previous studies showed that TREM-1 inhibition protects against lethality during experimental gram-negative sepsis. We here aimed to investigate the role of TREM-1 in an experimental model of pneumococcal pneumonia using TREM-1/3 deficient (Trem-1/3(-/-) ) and wild type (Wt) mice. Additionally ex vivo responsiveness of Trem-1/3(-/-n) eutrophils and macrophages was examined. S. pneumoniae infection resulted in a rapid recruitment of TREM-1 positive neutrophils into the bronchoalveolar space while high constitutive TREM-1 expression on alveolar macrophages remained unchanged. TREM-1/3 deficiency led to increased lethality accompanied by enhanced growth of S. pneumoniae at the primary site of infection and increased dissemination to distant organs. Within the first 3-6 hours of infection Trem-1/3(-/-m) ice demonstrated a strongly impaired innate immune response in the airways, as reflected by reduced local release of cytokines and chemokines and a delayed influx of neutrophils. Trem-1/3(-/-a) lveolar macrophages produced less cytokines upon exposure to S. pneumoniae in vitro and were less capable of phagocytosing this pathogen. TREM-1/3 deficiency did not influence neutrophil responsiveness to S. pneumoniae. These results identify TREM-1 as key player in protective innate immunity during pneumococcal pneumonia most likely by enhancing the early immune response of alveolar macrophages.
    The Journal of Pathology 08/2014; 233(4). DOI:10.1002/path.4361 · 7.43 Impact Factor
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    ABSTRACT: Streptococcus pneumoniae is a common cause of pneumonia and sepsis. Toll-like receptors (TLRs) play a pivotal role in the host defense against infection. In this study, we sought to determine the role of single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR a.k.a. TIR8), a negative regulator of TLR signaling, in pneumococcal pneumonia and sepsis. Wild-type and SIGIRR-deficient (sigirr-/-) mice were infected intranasally (to induce pneumonia) or intravenously (to induce primary sepsis) with S. pneumoniae and euthanized after 6, 24, or 48 h for analyses. Additionally, survival studies were performed. sigirr-/- mice showed delayed mortality during lethal pneumococcal pneumonia. Accordingly, sigirr-/- mice displayed lower bacterial loads in lungs and less dissemination of the infection 24 h after the induction of pneumonia. SIGIRR deficiency was associated with increased interstitial and perivascular inflammation in lung tissue early after infection, with no impact on neutrophil recruitment or cytokine production. sigirr-/- mice also demonstrated reduced bacterial burdens at multiple body sites during S. pneumoniae sepsis. sigirr-/- alveolar macrophages and neutrophils exhibited an increased capacity to phagocytose viable pneumococci. These results suggest that SIGIRR impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae. © 2014 S. Karger AG, Basel.
    Journal of Innate Immunity 02/2014; 6(4). DOI:10.1159/000358239 · 4.56 Impact Factor
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    ABSTRACT: Staphylococcus (S.) aureus has emerged as an important cause of necrotizing pneumonia. Lung injury during S. aureus pneumonia may be enhanced by local release of damage associated molecular patterns such as high-mobility group box 1 (HMGB1). In the current study we sought to determine the functional role of HMGB1 and its receptors, toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE), in the injurious host response to S. aureus pneumonia. Pneumonia was induced in wild type (Wt), TLR4 deficient (tlr4-/-) and RAGE deficient (rage-/-) mice by intranasal inoculation of 1 x 107 colony-forming units (CFU) of a USA300 S. aureus. In a separate set of experiments, Wt mice were injected intraperitoneally with a monoclonal anti-HMGB1 antibody or an isotype matched control antibody immediately before and every 24 hours after intranasal infection of S. aureus. Mice were sacrificed at 6, 24, 48 or 72 hours after infection for harvesting of blood and organs. S. aureus pneumonia was associated with HMGB1 release in the bronchoalveolar compartment peaking after 24 hours. Anti-HMGB1 attenuated lung pathology and protein leak and reduced interleukin-1beta release 6 hours after infection, but not at later time points. RAGE deficiency more modestly attenuated lung pathology without influencing protein leak, while TLR4 deficiency did not impact on lung injury. These data suggest that HMGB1 and RAGE, but not TLR4, contribute to lung injury accompanying the early phase of S. aureus pneumonia.
    Critical care (London, England) 12/2013; 17(6):R296. DOI:10.1186/cc13162
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    ABSTRACT: Background: Mast cells are implicated in allergic and innate immune responses in asthma, although their role in models using an allergen relevant for human disease is incompletely understood. House dust mite (HDM) allergy is common in asthma patients. Our aim was to investigate the role of mast cells in HDM-induced allergic lung inflammation. Methods: Wild-type (Wt) and mast cell-deficient Kit(w-sh) mice on a C57BL/6 background were repetitively exposed to HDM via the airways. Results: HDM challenge resulted in a rise in tryptase activity in bronchoalveolar lavage fluid (BALF) of Wt mice, indicative of mast cell activation. Kit(w-sh) mice showed a strongly attenuated HDM- induced recruitment of eosinophils in BALF and lung tissue, accompanied by reduced pulmonary levels of the eosinophil chemoattractant eotaxin. Remarkably, Kit(w-sh) mice demonstrated an unaltered capacity to develop lung pathology and increased mucus production in response to HDM. The increased plasma IgE in response to HDM in Wt mice was absent in Kit(w-sh) mice. Conclusion: These data contrast with previous reports on the role of mast cells in models using ovalbumin as allergen in that C57BL/6 Kit(w-sh) mice display a selective impairment of eosinophil recruitment without differences in other features of allergic inflammation. © 2013 S. Karger AG, Basel.
    Journal of Innate Immunity 10/2013; 6(2). DOI:10.1159/000354984 · 4.56 Impact Factor
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    ABSTRACT: Tuberculosis (TB), caused by Mycobacterium (M.) tuberculosis, is a devastating infectious disease causing many deaths world-wide. Thrombomodulin (TM) is a multidomain glycoprotein expressed on all vascular endothelial cells. We here studied the role of the lectin-like domain of TM, responsible for a variety of anti-inflammatory properties of TM, during TB. We compared the extent of TM-expression in human lung tissue of TB and control patients. The, the role of the lectin-like domain of TM was investigated by comparing mice lacking this domain (TMLeD/LeD mice) with wild-type (WT) mice during experimental lung TB induced by infection with M. tuberculosis via the airways. Lungs were harvested for analyses at two, six and 29 weeks after infection. Lung TM-expression was downregulated in TB patients, which was not related to changes in the amount of endothelium in infected lungs. TMLeD/LeD mice showed unaltered mycobacterial loads in lungs, liver and spleen during experimental TB. Additionally, lung histopathology and cytokine concentrations were largely similar in TMLeD/LeD and WT mice, while total leukocyte counts were increased in lungs of TMLeD/LeD mice after 29 weeks of infection. Mortality did not occur in either group. The lectin-like domain of TM does not play an important role in the host response to M. tuberculosis infection in mice.
    Thrombosis and Haemostasis 10/2013; 111(2). DOI:10.1160/TH13-08-0719 · 5.76 Impact Factor
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    ABSTRACT: Protease-activated receptor-2 (PAR2) is abundantly expressed in the pulmonary compartment. House dust mite (HDM) is a common cause of allergic asthma and contains multiple PAR2 agonistic proteases. The aim of this study was to determine the role of PAR2 in HDM-induced allergic lung inflammation. For this, the extent of allergic lung inflammation was studied in wild type (Wt) and PAR2 knockout (KO) mice after repeated airway exposure to HDM. HDM exposure of Wt mice resulted in a profound influx of eosinophils in bronchoalveolar lavage fluid (BALF) and accumulation of eosinophils in lung tissue, which both were strongly reduced in PAR2 KO mice. PAR2 KO mice demonstrated attenuated lung pathology and protein leak in the bronchoalveolar space, accompanied by lower BALF levels of the anaphylatoxins C3a and C5a. This study reveals, for the first time, an important role for PAR2 in allergic lung inflammation induced by the clinically relevant allergens contained in HDM.
    Innate Immunity 09/2013; 20(6). DOI:10.1177/1753425913503387 · 3.27 Impact Factor
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    ABSTRACT: Interleukin-1 receptor like 1 (ST2) has been implicated as a negative regulator of Toll-like receptor signaling. We here sought to elucidate the role of ST2 in cytokine release and systemic infection caused by two common human sepsis pathogens, Streptococcus (S.) pneumoniae (gram-positive) and Klebsiella (K.) pneumoniae (gram-negative). Whole blood leukocytes and splenocytes were harvested from ST2 deficient (st2) and wild type (WT) mice and stimulated ex vivo with S. pneumoniae or K. pneumoniae. In addition, st2 and WT mice were infected intravenously with these bacteria and bacterial loads and cytokine levels were measured in blood, spleens and lungs at 6, 24 and 48 hours thereafter. Unexpectedly, st2 blood leukocytes and splenocytes produced lower levels of cytokines and chemokines than WT cells in response to either pathogen. In contrast, the in vivo role of ST2 during sepsis caused by these bacteria was limited, although at 6 and 24 hours after infection with S. pneumoniae bacterial loads were lower in spleens of st2 mice. ST2 augments rather than inhibits cytokine release by blood leukocytes and splenocytes exposed to S. pneumoniae or K. pneumoniae, but plays a limited role in host defense during sepsis caused by these pathogens.
    Shock (Augusta, Ga.) 07/2013; DOI:10.1097/SHK.0b013e3182a35f02 · 2.73 Impact Factor
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    ABSTRACT: Streptococcus pneumoniae is one of the most common causes of sepsis. Sepsis is associated with the release of 'damage-associated molecular patterns' (DAMPs). The receptor for advanced glycation end products (RAGE) is a multiligand receptor, abundantly expressed in the lungs, that recognizes several of these DAMPs. Triggering of RAGE leads to activation of the NF-κB pathway and perpetuation of inflammation. Earlier investigations have shown that the absence of RAGE reduces inflammation and bacterial dissemination and increases survival in sepsis caused by S. pneumoniae pneumonia. We hypothesized that the detrimental role of RAGE depends on the level of RAGE expression in the primary organ of infection. By directly injecting S. pneumoniae intravenously, thereby circumventing the extensive RAGE-expressing lung, we here determined whether RAGE contributes to an adverse outcome of bacteremia or whether its role is restricted to primary lung infection. During late-stage infection (48 h), rage(-/-) mice had an attenuated systemic inflammatory response, as reflected by lower plasma levels of proinflammatory cytokines, reduced endothelial cell activation (as measured by E-selectin levels) and less neutrophil accumulation in lung tissue. However, RAGE deficiency did not influence bacterial loads or survival in this model. In accordance, plasma markers for cell injury were similar in both mouse strains. These results demonstrate that while RAGE plays a harmful part in S. pneumoniae sepsis originating from the respiratory tract, this receptor has a limited role in the outcome of primary bloodstream infection by this pathogen.
    Journal of Innate Immunity 06/2013; 5(6). DOI:10.1159/000348739 · 4.56 Impact Factor
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    ABSTRACT: Interleukin-1 receptor like 1 (ST2) is a negative regulator of Toll-like receptor (TLR) signaling. TLRs are important for host defense during respiratory tract infections by both influenza and Streptococcus (S.) pneumoniae. Enhanced susceptibility to pneumococcal pneumonia is an important complication following influenza virus infection. We here sought to determine the role of ST2 in primary influenza A infection and secondary pneumococcal pneumonia. ST2 knockout (st2 -/-) and wild-type (WT) mice were intranasally infected with influenza A virus; in some experiments mice were infected 2 weeks later with S. pneumoniae. Both mouse strains cleared the virus similarly during the first 14 days of influenza infection and had recovered their weights equally at day 14. Overall st2-/- mice tended to have a stronger pulmonary inflammatory response upon infection with influenza; especially 14 days after infection modest but statistically significant elevations were seen in lung IL-6, IL-1β, KC, IL-10, and IL-33 concentrations and myeloperoxidase levels, indicative of enhanced neutrophil activity. Interestingly, bacterial lung loads were higher in st2-/- mice during the later stages of secondary pneumococcal pneumonia, which was associated with relatively increased lung IFN-γ levels. ST2 deficiency did not impact on gross lung pathology in either influenza or secondary S. pneumoniae pneumonia. These data show that ST2 plays a limited anti-inflammatory role during both primary influenza and postinfluenza pneumococcal pneumonia.
    PLoS ONE 03/2013; 8(3):e58191. DOI:10.1371/journal.pone.0058191 · 3.23 Impact Factor

Publication Stats

2k Citations
564.31 Total Impact Points


  • 2006–2015
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2005–2014
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Center for Infection and Immunity Amsterdam
      • • Center for Experimental and Molecular Medicine
      • • Academic Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2007
    • Universität Konstanz
      Constance, Baden-Württemberg, Germany
    • University of Oxford
      Oxford, England, United Kingdom
  • 2002
    • Erasmus Universiteit Rotterdam
      • Department of Immunology
      Rotterdam, South Holland, Netherlands