The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Michael A Matthay - One of the best experts on this subject based on the ideXlab platform.
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The TLR4‐PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia
Stem Cells, 2018Co-Authors: Naveen Gupta, Anna Krasnodembskaya, Michael A Matthay, Ranjeet Kumar Sinha, Xiao Xu, Victor Nizet, John H. GriffinAbstract:Bone marrow derived mesenchymal stromal cells have been shown to have significant therapeutic effects in experimental models of Pneumonia and lung injury. The current study examined the roles of the toll like receptor 4 (TLR4) and protease activated receptor 1 (PAR1) pathways on mesenchymal stromal cell (MSC) survival and therapeutic activity in a murine model of Pneumonia. MSCs from TLR4 -/- and R41Q-PAR1 mutated mice were isolated to test the effect of mutating these specific pathways on MSC survival when exposed to cytotoxic stimuli in vitro. An Escherichia Coli Pneumonia model was used to assess the effect of these specific pathways on MSC therapeutic activity in vivo. Our results showed that mutation of either the TLR4 or PAR1 pathways in MSCs impaired cell survival under conditions of inflammatory stress in vitro, and eliminated their therapeutic efficacy in vivo. Also, stimulation of the TLR4 pathway on MSCs led to secretion of low levels of prothrombin by MSCs, while disrupting the TLR4 pathway impaired canonical signaling through PAR1 in response to thrombin. Therefore, this study demonstrates that both TLR4 and PAR1 are required for MSC survival under inflammatory conditions in vitro and therapeutic capacity in vivo, and that the TLR4 pathway regulates signaling through PAR1 on MSCs. Stem Cells 2018;36:796-806.
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Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS
Stem Cells, 2016Co-Authors: Megan Jackson, Michael A Matthay, Thomas Morrison, Declan Doherty, Daniel F. Mcauley, Adrien Kissenpfennig, Cecilia O'kane, Anna KrasnodembskayaAbstract:Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia Coli Pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte-derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)-like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210–2223
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Therapeutic Effects of Human Mesenchymal Stem Cell–derived Microvesicles in Severe Pneumonia in Mice
American Journal of Respiratory and Critical Care Medicine, 2015Co-Authors: Antoine Monsel, Stephane Gennai, Shuling Hu, Jeanjacques Rouby, Michelle Rosenzwajg, Michael A MatthayAbstract:Rationale: Microvesicles (MVs) are anuclear fragments of cells released from the endosomal compartment or shed from surface membranes. We and other investigators demonstrated that MVs released by mesenchymal stem cells (MSCs) were as effective as the cells themselves in inflammatory injuries, such as after endotoxin-induced acute lung injury. However, the therapeutic effects of MVs in an infectious model of acute lung injury remain unknown.Objectives: We investigated the effects of human MSC MVs on lung inflammation, protein permeability, bacterial clearance, and survival after severe bacterial Pneumonia.Methods: We tested the effects of MVs derived from human MSCs on Escherichia Coli Pneumonia in mice. We also studied the interactions between MVs and human monocytes and human alveolar epithelial type 2 cells.Measurements and Main Results: Administration of MVs derived from human MSCs improved survival in part through keratinocyte growth factor secretion and decreased the influx of inflammatory cells, cyt...
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therapeutic effects of human mesenchymal stem cell derived microvesicles in severe Pneumonia in mice
American Journal of Respiratory and Critical Care Medicine, 2015Co-Authors: Antoine Monsel, Stephane Gennai, Shuling Hu, Jeanjacques Rouby, Michelle Rosenzwajg, Michael A MatthayAbstract:Rationale: Microvesicles (MVs) are anuclear fragments of cells released from the endosomal compartment or shed from surface membranes. We and other investigators demonstrated that MVs released by mesenchymal stem cells (MSCs) were as effective as the cells themselves in inflammatory injuries, such as after endotoxin-induced acute lung injury. However, the therapeutic effects of MVs in an infectious model of acute lung injury remain unknown.Objectives: We investigated the effects of human MSC MVs on lung inflammation, protein permeability, bacterial clearance, and survival after severe bacterial Pneumonia.Methods: We tested the effects of MVs derived from human MSCs on Escherichia Coli Pneumonia in mice. We also studied the interactions between MVs and human monocytes and human alveolar epithelial type 2 cells.Measurements and Main Results: Administration of MVs derived from human MSCs improved survival in part through keratinocyte growth factor secretion and decreased the influx of inflammatory cells, cyt...
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Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria
American Journal of Respiratory and Critical Care Medicine, 2013Co-Authors: Anna Krasnodembskaya, David H. Mckenna, Yuanlin Song, Jason Abbott, Michael A MatthayAbstract:Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells’ immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury.Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance.Methods: We developed an Escherichia Coli Pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury.Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyt...
Joseph P Mizgerd - One of the best experts on this subject based on the ideXlab platform.
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valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia Coli Pneumonia at the expense of bacterial clearance
Journal of Trauma-injury Infection and Critical Care, 2017Co-Authors: George Kasotakis, Joseph P Mizgerd, Manuel D Galvan, Elizabeth G King, Beda Sarkar, Arthur F Stucchi, Peter A Burke, Daniel G RemickAbstract:BACKGROUND Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti-inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia Coli Pneumonia-induced ARDS. METHODS ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 × 106E. Coli. VPA (250 mg/kg) was administered 30 minutes after E. Coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid. RESULTS VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma. CONCLUSION Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth.
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alveolar epithelial stat3 il 6 family cytokines and host defense during Escherichia Coli Pneumonia
American Journal of Respiratory Cell and Molecular Biology, 2008Co-Authors: Lee J Quinton, Matthew R Jones, Bryanne E Robson, Benjamin T Simms, Jeffrey A Whitsett, Joseph P MizgerdAbstract:While signal transducer and activator of transcription (STAT) 3 signaling has been linked to multiple pathways influencing immune function and cell survival, the direct influence of this transcription factor on innate immunity and tissue homeostasis during Pneumonia is unknown. Human patients with dominant-negative mutations in the Stat3 gene develop recurrent Pneumonias, suggesting a role for STAT3 in pulmonary host defense. We hypothesized that alveolar epithelial STAT3 is activated by IL-6 family cytokines and is required for effective responses during gram-negative bacterial Pneumonia. STAT3 phosphorylation was increased in pneumonic mouse lungs and in murine lung epithelial (MLE)-15 cells stimulated with pneumonic bronchoalveolar lavage fluid (BALF) through 48 hours of Escherichia Coli Pneumonia. Mice lacking active STAT3 in alveolar epithelial cells (Stat3Δ/Δ) had fewer alveolar neutrophils and more viable bacteria than control mice early after intratracheal E. Coli. By 48 hours after E. Coli infection, however, lung injury was increased in Stat3Δ/Δ mice. Bacteria were cleared from lungs of both genotypes, albeit more slowly in Stat3Δ/Δ mice. Of the IL-6 family cytokines measured in lungs from infected C57BL/6 mice, IL-6, oncostatin M, leukemia inhibitory factor (LIF), and IL-11 were significantly elevated. Neutralization studies demonstrated that LIF and IL-6 mediated BALF-induced STAT3 activation in MLE-15 cells. Together, these results indicate that during E. Coli Pneumonia, select IL-6 family members activate alveolar epithelial STAT3, which functions to promote neutrophil recruitment and to limit both infection and lung injury.
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roles of interleukin 6 in activation of stat proteins and recruitment of neutrophils during Escherichia Coli Pneumonia
The Journal of Infectious Diseases, 2006Co-Authors: Matthew R Jones, Lee J Quinton, Benjamin T Simms, Michal M Lupa, Mariya S Kogan, Joseph P MizgerdAbstract:Lower respiratory tract infections are the leading cause of disability-adjusted life years lost worldwide [1] and are the leading cause of hospitalizations and deaths due to infection in the United States [2, 3]. Gram-negative bacterial rods are common causes of Pneumonia in hospitals and nursing homes [4, 5] and have especially high mortality rates [6, 7]. The cytokine interleukin (IL)–6 is induced by a wide variety of infections. During community-acquired Pneumonia, IL-6 concentrations in patients’ blood and bronchoalveolar lavage (BAL) fluid are positively associated with the severity of disease [8–10]. During experimental Streptococcus Pneumoniae infection in mice, IL-6 deficiency due to gene targeting increases bacterial burdens and mortality [11]. Thus, IL-6 improves defenses against S. Pneumoniae in the lungs, although the responses regulated by IL-6 that are essential to the antipneumococcal host defenses remain to be determined. Neutrophil recruitment is essential to effective host defenses against bacteria, particularly gram-negative rods, in the lungs [12, 13]. Maximal neutrophil recruitment in the lungs requires the induction of IL-6 in response to some purified bacterial products, such as peptidoglycan or pneumolysin [14, 15], but not to others, such as lipoteichoic acid or lipopolysaccharide [15, 16]. The roles that IL-6 plays in modulating neutrophil recruitment elicited by living bacteria in the lungs have yet to be identified. Furthermore, whether IL-6 impacts the host defenses against gram-negative bacteria in the lungs remains to be determined. We hypothesized that IL-6 makes essential contributions to the host defenses during E. Coli Pneumonia, and we tested this hypothesis using IL-6–deficient mice.
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NF-κB p50 facilitates neutrophil accumulation during LPS-induced pulmonary inflammation
BMC Immunology, 2004Co-Authors: Joseph P Mizgerd, Michal M Lupa, Matt S SpiekerAbstract:Background Transcription factors have distinct functions in regulating immune responses. During Escherichia Coli Pneumonia, deficiency of NF-κB p50 increases gene expression and neutrophil recruitment, suggesting that p50 normally limits these innate immune responses. p50-deficient mice were used to determine how p50 regulates responses to a simpler, non-viable bacterial stimulus in the lungs, E. Coli lipopolysaccharide (LPS). Results In contrast to previous results with living E. Coli , neutrophil accumulation elicited by E. Coli LPS in the lungs was decreased by p50 deficiency, to approximately 30% of wild type levels. Heat-killed E. Coli induced neutrophil accumulation which was not decreased by p50 deficiency, demonstrating that bacterial growth and metabolism were not responsible for the different responses to bacteria and LPS. p50 deficiency increased the LPS-induced expression of κB-regulated genes essential to neutrophil recruitment, including KC, MIP-2, ICAM-1, and TNF-α suggesting that p50 normally limited this gene expression and that decreased neutrophil recruitment did not result from insufficient expression of these genes. Neutrophils were responsive to the chemokine KC in the peripheral blood of p50-deficient mice with or without LPS-induced pulmonary inflammation. Interleukin-6 (IL-6), previously demonstrated to decrease LPS-induced neutrophil recruitment in the lungs, was increased by p50 deficiency, but LPS-induced neutrophil recruitment was decreased by p50 deficiency even in IL-6 deficient mice. Conclusion p50 makes essential contributions to neutrophil accumulation elicited by LPS in the lungs. This p50-dependent pathway for neutrophil accumulation can be overcome by bacterial products other than LPS and does not require IL-6.
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roles for early response cytokines during Escherichia Coli Pneumonia revealed by mice with combined deficiencies of all signaling receptors for tnf and il 1
American Journal of Physiology-lung Cellular and Molecular Physiology, 2004Co-Authors: Joseph P Mizgerd, Michal M Lupa, Josephine Hjoberg, Joseph Vallone, Henry B Warren, James P Butler, Eric S SilvermanAbstract:During infection, inflammation is essential for host defense, but it can injure tissues and compromise organ function. TNF-α and IL-1 (α and β) are early response cytokines that facilitate inflammation. To determine the roles of these cytokines with overlapping functions, we generated mice deficient in all of the three receptors mediating their effects (TNFR1, TNFR2, and IL-1RI). During Escherichia Coli Pneumonia, receptor deficiency decreased neutrophil recruitment and edema accumulation to half of the levels observed in wild-type mice. Thus these receptors contributed to maximal responses, but substantial inflammation progressed independently of them. Receptor deficiency compromised antibacterial efficacy for some infectious doses. Decreased ventilation during E. Coli Pneumonia was not affected by receptor deficiency. However, the loss of lung compliance during Pneumonia was substantially attenuated by receptor deficiency. Thus during E. Coli Pneumonia in mice, the lack of signaling from TNF-α and IL-1 ...
Scott G Worthen - One of the best experts on this subject based on the ideXlab platform.
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cxcl5 regulates chemokine scavenging and pulmonary host defense to bacterial infection
Immunity, 2010Co-Authors: Michael Favara, Teshell K Greene, Mortimer Poncz, Scott G Worthen, Samithamby JeyaseelanAbstract:The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia Coli Pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.
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myeloid differentiation protein 2 dependent and independent neutrophil accumulation during Escherichia Coli Pneumonia
American Journal of Respiratory Cell and Molecular Biology, 2009Co-Authors: Rachel L Zemans, Scott G Worthen, Samithamby Jeyaseelan, Scott K YoungAbstract:Bacterial Pneumonia remains a serious disease. Pattern recognition receptors play an integral role in neutrophil accumulation during Pneumonia. Although myeloid differentiation protein (MD)-2 has been recognized as a key molecule for LPS signaling, the role of MD-2 in neutrophil accumulation in the lung during bacterial infection has not been explored. Here, we investigate the role of MD-2 in Escherichia Coli LPS–induced lung inflammation and E. Coli–induced Pneumonia. LPS-induced CD14-independent neutrophil accumulation was abolished in CD14/MD-2−/− mice. MD-2−/− mice challenged with LPS displayed attenuated neutrophil influx, NF-κB activation, cytokine/chemokine expression, and lung histopathology. MD-2−/− mice transplanted with MD-2+/+ bone marrow demonstrated decreased neutrophil influx and cytokine/chemokine expression in the lungs when challenged by LPS. MD-2−/− mice infected with E. Coli demonstrated reduced neutrophil influx and cytokine/chemokine expression in the lungs, whereas heat-killed E. Coli did not induce either neutrophil accumulation or cytokine/chemokine expression in MD-2−/− mice infected with E. Coli. Furthermore, MD-2−/− mice displayed increased bacterial burden in the lungs and enhanced bacterial dissemination. Toll-like receptor (TLR)-5−/− mice infected with E. Coli exhibited attenuated neutrophil accumulation, whereas MD-2/TLR5−/− mice inoculated with E. Coli showed further attenuated neutrophil influx and impaired bacterial clearance. Taken together, these new findings demonstrate: (1) the important role of MD-2 in the CD14-independent LPS-mediated cascade of neutrophil influx; (2) the relative importance of bone marrow– and non–bone marrow cell–derived MD-2 in LPS-induced inflammation; and (3) the essential role of MD-2–dependent and MD-2–independent (TLR5) signaling in E. Coli–induced neutrophil accumulation and pulmonary host defense.
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toll il 1 receptor domain containing adaptor inducing ifn β trif mediated signaling contributes to innate immune responses in the lung during Escherichia Coli Pneumonia
Journal of Immunology, 2007Co-Authors: Samithamby Jeyaseelan, Scott K Young, Michael B Fessler, Kenneth C Malcolm, Masahiro Yamamoto, Shizuo Akira, Scott G WorthenAbstract:Bacterial Pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia Coli Pneumonia. TRIF −/− mice infected with E. Coli display attenuated neutrophil migration; NF-κB activation; and TNF-α, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. Coli -induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF +/+ mice, but attenuated in BMMs of TRIF −/− mice. Furthermore, E. Coli -induced TNF-α and IL-6 production was attenuated in BMMs of TRIF −/− mice. E. Coli LPS-induced late MAPK activation, and TNF-α and IL-6 production were abolished in BMMs of TRIF −/− mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3 −/− mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. Coli Pneumonia. A TLR4-blocking Ab inhibited E. Coli -induced TNF-α and IL-6 in BMMs of both TRIF −/− and TRIF +/+ mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. Coli burden in the lungs and E. Coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.
Samithamby Jeyaseelan - One of the best experts on this subject based on the ideXlab platform.
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cxcl5 regulates chemokine scavenging and pulmonary host defense to bacterial infection
Immunity, 2010Co-Authors: Michael Favara, Teshell K Greene, Mortimer Poncz, Scott G Worthen, Samithamby JeyaseelanAbstract:The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia Coli Pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.
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myeloid differentiation protein 2 dependent and independent neutrophil accumulation during Escherichia Coli Pneumonia
American Journal of Respiratory Cell and Molecular Biology, 2009Co-Authors: Rachel L Zemans, Scott G Worthen, Samithamby Jeyaseelan, Scott K YoungAbstract:Bacterial Pneumonia remains a serious disease. Pattern recognition receptors play an integral role in neutrophil accumulation during Pneumonia. Although myeloid differentiation protein (MD)-2 has been recognized as a key molecule for LPS signaling, the role of MD-2 in neutrophil accumulation in the lung during bacterial infection has not been explored. Here, we investigate the role of MD-2 in Escherichia Coli LPS–induced lung inflammation and E. Coli–induced Pneumonia. LPS-induced CD14-independent neutrophil accumulation was abolished in CD14/MD-2−/− mice. MD-2−/− mice challenged with LPS displayed attenuated neutrophil influx, NF-κB activation, cytokine/chemokine expression, and lung histopathology. MD-2−/− mice transplanted with MD-2+/+ bone marrow demonstrated decreased neutrophil influx and cytokine/chemokine expression in the lungs when challenged by LPS. MD-2−/− mice infected with E. Coli demonstrated reduced neutrophil influx and cytokine/chemokine expression in the lungs, whereas heat-killed E. Coli did not induce either neutrophil accumulation or cytokine/chemokine expression in MD-2−/− mice infected with E. Coli. Furthermore, MD-2−/− mice displayed increased bacterial burden in the lungs and enhanced bacterial dissemination. Toll-like receptor (TLR)-5−/− mice infected with E. Coli exhibited attenuated neutrophil accumulation, whereas MD-2/TLR5−/− mice inoculated with E. Coli showed further attenuated neutrophil influx and impaired bacterial clearance. Taken together, these new findings demonstrate: (1) the important role of MD-2 in the CD14-independent LPS-mediated cascade of neutrophil influx; (2) the relative importance of bone marrow– and non–bone marrow cell–derived MD-2 in LPS-induced inflammation; and (3) the essential role of MD-2–dependent and MD-2–independent (TLR5) signaling in E. Coli–induced neutrophil accumulation and pulmonary host defense.
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toll il 1 receptor domain containing adaptor inducing ifn β trif mediated signaling contributes to innate immune responses in the lung during Escherichia Coli Pneumonia
Journal of Immunology, 2007Co-Authors: Samithamby Jeyaseelan, Scott K Young, Michael B Fessler, Kenneth C Malcolm, Masahiro Yamamoto, Shizuo Akira, Scott G WorthenAbstract:Bacterial Pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia Coli Pneumonia. TRIF −/− mice infected with E. Coli display attenuated neutrophil migration; NF-κB activation; and TNF-α, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. Coli -induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF +/+ mice, but attenuated in BMMs of TRIF −/− mice. Furthermore, E. Coli -induced TNF-α and IL-6 production was attenuated in BMMs of TRIF −/− mice. E. Coli LPS-induced late MAPK activation, and TNF-α and IL-6 production were abolished in BMMs of TRIF −/− mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3 −/− mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. Coli Pneumonia. A TLR4-blocking Ab inhibited E. Coli -induced TNF-α and IL-6 in BMMs of both TRIF −/− and TRIF +/+ mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. Coli burden in the lungs and E. Coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.
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Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β (TRIF)-Mediated Signaling Contributes to Innate Immune Responses in the Lung during Escherichia Coli Pneumonia
Journal of Immunology, 2007Co-Authors: Samithamby Jeyaseelan, Scott K Young, Michael B Fessler, Kenneth C Malcolm, Masahiro Yamamoto, Shizuo Akira, G. Scott WorthenAbstract:Bacterial Pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia Coli Pneumonia. TRIF −/− mice infected with E. Coli display attenuated neutrophil migration; NF-κB activation; and TNF-α, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. Coli -induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF +/+ mice, but attenuated in BMMs of TRIF −/− mice. Furthermore, E. Coli -induced TNF-α and IL-6 production was attenuated in BMMs of TRIF −/− mice. E. Coli LPS-induced late MAPK activation, and TNF-α and IL-6 production were abolished in BMMs of TRIF −/− mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3 −/− mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. Coli Pneumonia. A TLR4-blocking Ab inhibited E. Coli -induced TNF-α and IL-6 in BMMs of both TRIF −/− and TRIF +/+ mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. Coli burden in the lungs and E. Coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.
Claire M Doerschuk - One of the best experts on this subject based on the ideXlab platform.
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cd44 deficiency leads to enhanced neutrophil migration and lung injury in Escherichia Coli Pneumonia in mice
American Journal of Pathology, 2002Co-Authors: Qin Wang, Priit Teder, Nancy P Judd, Paul W Noble, Claire M DoerschukAbstract:CD44 is a major cell-surface receptor for hyaluronic acid (HA), a glycosaminoglycan component of extracellular matrix. HA-CD44 interactions have been implicated in leukocyte extravasation into an inflammatory site. This study examined the role of CD44 in acute inflammatory responses during Pneumonias induced by Escherichia Coli and Streptococcus Pneumoniae using CD44-deficient mice. In E. Coli-induced Pneumonia, neutrophil accumulation in the lungs and edema formation was increased by 84% and 88%, respectively, in CD44-deficient mice compared to wild-type mice. In contrast, no difference was observed between these genotypes in S. Pneumoniae-induced Pneumonia, and the HA content in the lungs decreased after instillation of S. Pneumoniae, but not E. Coli, in both genotypes. Studies to determine the mechanisms for this enhanced response showed that: 1) neutrophil apoptosis was not different between these two genotypes in either type of Pneumonia; 2) CD44 deficiency resulted in enhanced mRNA expression of several inflammatory genes; and 3) CD44-deficient neutrophils migrated through Matrigel in response to chemoattractants faster and in greater numbers than wild-type neutrophils in vitro and this increase was in part dependent on HA content in the Matrigel. These data demonstrate that CD44 deficiency results in enhanced inflammation in E. Coli but not S. Pneumoniae-induced Pneumonia, suggesting a previously unrecognized role for CD44 in limiting the inflammatory response to E. Coli.
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early response cytokines and innate immunity essential roles for tnf receptor 1 and type i il 1 receptor during Escherichia Coli Pneumonia in mice
Journal of Immunology, 2001Co-Authors: Joseph P Mizgerd, Matt R Spieker, Claire M DoerschukAbstract:The early response cytokines, TNF and IL-1, have overlapping biologic effects that may function to propagate, amplify, and coordinate host responses to microbial challenges. To determine whether signaling from these early response cytokines is essential to orchestrating innate immune responses to intrapulmonary bacteria, the early inflammatory events induced by instillation of Escherichia Coli into the lungs were compared in wild-type (WT) mice and mice deficient in both TNF receptor 1 (TNFR1) and the type I IL-1 receptor (IL1R1). Neutrophil emigration and edema accumulation induced by E. Coli were significantly compromised by TNFR1/IL1R1 deficiency. Neutrophil numbers in the circulation and within alveolar septae did not differ between WT and TNFR1/IL1R1 mice, suggesting that decreased neutrophil emigration did not result from decreased sequestration or delivery of intravascular neutrophils. The nuclear translocation of NF-κB and the expression of the chemokine macrophage inflammatory protein-2 did not differ between WT and TNFR1/IL1R1 lungs. However, the concentration of the chemokine KC was significantly decreased in the bronchoalveolar lavage fluids of TNFR1/IL1R1 mice compared with that in WT mice. Thus, while many of the molecular and cellular responses to E. Coli in the lungs did not require signaling by either TNFR1 or IL1R1, early response cytokine signaling was critical to KC expression in the pulmonary air spaces and neutrophil emigration from the alveolar septae.
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roles of tumor necrosis factor receptor signaling during murine Escherichia Coli Pneumonia
American Journal of Respiratory Cell and Molecular Biology, 2000Co-Authors: Joseph P Mizgerd, Jacques J Peschon, Claire M DoerschukAbstract:We hypothesized that tumor necrosis factor (TNF)- a signaling is essential to inflammation and host defense during Escherichia Coli Pneumonia. We tested this hypothesis by instilling E. Coli into the lungs of wild-type (WT) mice and gene-targeted mice that lack both p55 and p75 receptors for TNF- a . The emigration of neutrophils 6 h after instillation of E. Coli was not decreased, but rather was significantly increased (167% of WT), in TNF receptor (TNFR)‐deficient mice. This increased neutrophil emigration did not result from peripheral blood neutrophilia or enhanced neutrophil sequestration, inasmuch as the numbers of neutrophils in the circulating blood and in the pulmonary capillaries did not differ between TNFR-deficient and WT mice. The accumulation of pulmonary edema fluid was not inhibited in TNFR-deficient compared with WT mice. Nuclear factor- k B (NF- k B) translocation in the lungs was not prevented in TNFRdeficient mice. Thus, signaling pathways independent of TNFRs can mediate the acute inflammatory response during E. Coli Pneumonia. However, despite this inflammatory response, bacterial clearance was impaired in TNFR-deficient mice (109 6 8% versus 51 6 14% of the original inoculum viable after 6 h in TNFR-deficient and WT mice, respectively). Increased neutrophil emigration during E. Coli Pneumonia in TNFR-deficient mice may thus result from an increased bacterial burden in the lungs. During acute E. Coli Pneumonia, the absence of TNFR signaling compromised bacterial killing, but did not prevent inflammation, as measured by the accumulation of edema fluid and neutrophils. Mizgerd, J. P., J. J. Peschon, and C. M. Doerschuk. 2000. Roles of tumor necrosis factor receptor signaling during murine Escherichia Coli Pneumonia. Am. J. Respir. Cell Mol. Biol. 22:85‐91 .
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Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice.
Journal of Experimental Medicine, 1997Co-Authors: Joseph P Mizgerd, Hiroshi Kubo, Gregory J. Kutkoski, Sabrina D. Bhagwan, Karin Scharffetter-kochanek, Arthur L. Beaudet, Claire M DoerschukAbstract:To determine the role of CD11/CD18 complexes in neutrophil emigration, inflammation was induced in the skin, lungs, or peritoneum of mutant mice deficient in CD18 (CD18−/− mutants). Peripheral blood of CD18−/− mutants contained 11-fold more neutrophils than did blood of wild-type (WT) mice. During irritant dermatitis induced by topical application of croton oil, the number of emigrated neutrophils in histological sections of dermis was 98% less in CD18−/− mutants than in WT mice. During Streptococcus Pneumoniae Pneumonia, neutrophil emigration in CD18−/− mutants was not reduced. These data are consistent with expectations based on studies using blocking antibodies to inhibit CD11/CD18 complexes, and on observations of humans lacking CD11/CD18 complexes. The number of emigrated neutrophils in lung sections during Escherichia Coli Pneumonia, or in peritoneal lavage fluid after 4 h of S. Pneumoniae peritonitis, was not reduced in CD18−/− mutants, but rather was greater than the WT values (240 ± 30 and 220 ± 30% WT, respectively). Also, there was no inhibition of neutrophil emigration during sterile peritonitis induced by intraperitoneal injection of thioglycollate (90 ± 20% WT). These data contrast with expectations. Whereas CD11/CD18 complexes are essential to the dermal emigration of neutrophils during acute dermatitis, CD18−/− mutant mice demonstrate surprising alternative pathways for neutrophil emigration during Pneumonia or peritonitis.