151 results on '"Kubes, Paul"'
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2. Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever.
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Jorch, Selina K., McNally, Annika, Berger, Philipp, Wolf, Jonas, Kaiser, Kim, Chetrusca Covash, Andrian, Robeck, Stefanie, Pastau, Isabell, Fehler, Olesja, Jauch-Speer, Saskia-L., Hermann, Sven, Schäfers, Michael, Van Gorp, Hanne, Kanneganti, Apurva, Dehoorne, Joke, Haerynck, Filomeen, Penco, Federica, Gattorno, Marco, Chae, Jae Jin, and Kubes, Paul
- Abstract
[Display omitted] Familial Mediterranean fever (FMF), caused by mutations in the pyrin-encoding MEFV gene, is characterized by uncontrolled caspase-1 activation and IL-1β secretion. A similar mechanism drives inflammation in cryopyrin-associated periodic fever syndrome (CAPS) caused by mutations in NLRP3. CAPS and FMF, however, result in largely different clinical manifestations, pointing to additional, autoinflammatory pathways involved in FMF. Another hallmark of FMF is extraordinarily high expression of S100A8 and S100A9. These alarmins are ligands of Toll-like receptor 4 and amplifiers of inflammation. However, the relevance of this inflammatory pathway for the pathogenesis of FMF is unknown. This study investigated whether mutations in pyrin result in specific secretion of S100A8/A9 alarmins through gasdermin D pores' amplifying FMF pathology. S100A8/A9 levels in FMF patients were quantified by enzyme-linked immunosorbent assay. In vitro models with knockout cell lines and specific protein inhibitors were used to unravel the S100A8/A9 secretion mechanism. The impact of S100A8/A9 to the pathophysiology of FMF was analyzed with FMF (MEFV
V726A/V726A ) and S100A9−/− mouse models. Pyrin-S100A8/A9 interaction was investigated by coimmunoprecipitation, immunofluorescence, and enzyme-linked immunosorbent assay studies. The S100A8/A9 complexes directly interacted with pyrin. Knocking out pyrin, caspase-1, or gasdermin D inhibited the secretion of these S100 alarmins. Inflammatory S100A8/A9 dimers were inactivated by tetramer formation. Blocking this inactivation by targeted S100A9 deletion in a murine FMF model demonstrated the relevance of this novel autoinflammatory pathway in FMF. This is the first proof that members of the S100 alarmin family are released in a pyrin/caspase-1/gasdermin D–dependent pathway and directly drive autoinflammation in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. Intravital imaging of three different microvascular beds in SARS-CoV-2–infected mice
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Castanheira, Fernanda V. S., Nguyen, Rita, Willson, Michelle, Davoli-Ferreira, Marcela, David, Bruna A., Kelly, Margaret M., Lee, Woo-Yong, Kratofil, Rachel M., Zhang, Wen X., Bui-Marinos, Maxwell, Corcoran, Jennifer A., and Kubes, Paul
- Abstract
•In vivo imaging of neon-green SARS-CoV-2–infected mice shows infected epithelium and endothelium in the lung, and neurons in the brain.•In vivo imaging shows that thrombosis and inflammation are prevalent in the brain and lungs of infected mice.
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- 2023
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4. Neutrophils in host defense, healing, and hypersensitivity: Dynamic cells within a dynamic host.
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Siwicki, Marie and Kubes, Paul
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Neutrophils are cells of the innate immune system that are extremely abundant in vivo and respond quickly to infection, injury, and inflammation. Their constant circulation throughout the body makes them some of the first responders to infection, and indeed they play a critical role in host defense against bacterial and fungal pathogens. It is now appreciated that neutrophils also play an important role in tissue healing after injury. Their short life cycle, rapid response kinetics, and vast numbers make neutrophils a highly dynamic and potentially extremely influential cell population. It has become clear that they are highly integrated with other cells of the immune system and can thus exert critical effects on the course of an inflammatory response; they can further impact tissue homeostasis and recovery after challenge. In this review, we discuss the fundamentals of neutrophils in host defense and healing; we explore the relationship between neutrophils and the dynamic host environment, including circadian cycles and the microbiome; we survey the field of neutrophils in asthma and allergy; and we consider the question of neutrophil heterogeneity—namely, whether there could be specific subsets of neutrophils that perform different functions in vivo. [ABSTRACT FROM AUTHOR]
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- 2023
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5. A monocyte–leptin–angiogenesis pathway critical for repair post-infection
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Kratofil, Rachel M., Shim, Hanjoo B., Shim, Raymond, Lee, Woo Yong, Labit, Elodie, Sinha, Sarthak, Keenan, Catherine M., Surewaard, Bas G. J., Noh, Ji Yeon, Sun, Yuxiang, Sharkey, Keith A., Mack, Matthias, Biernaskie, Jeff, Deniset, Justin F., and Kubes, Paul
- Abstract
During infection, inflammatory monocytes are thought to be key for bacterial eradication, but this is hard to reconcile with the large numbers of neutrophils that are recruited for each monocyte that migrates to the afflicted tissue, and the much more robust microbicidal functions of the neutrophils. However, unlike neutrophils, monocytes have the capacity to convert to situationally specific macrophages that may have critical functions beyond infection control1,2. Here, using a foreign body coated with Staphylococcus aureusand imaging over time from cutaneous infection to wound resolution, we show that monocytes and neutrophils are recruited in similar numbers with low-dose infection but not with high-dose infection, and form a localization pattern in which monocytes surround the infection site, whereas neutrophils infiltrate it. Monocytes did not contribute to bacterial clearance but converted to macrophages that persisted for weeks after infection, regulating hypodermal adipocyte expansion and production of the adipokine hormone leptin. In infected monocyte-deficient mice there was increased persistent hypodermis thickening and an elevated leptin level, which drove overgrowth of dysfunctional blood vasculature and delayed healing, with a thickened scar. Ghrelin, which opposes leptin function3, was produced locally by monocytes, and reduced vascular overgrowth and improved healing post-infection. In sum, we find that monocytes function as a cellular rheostat by regulating leptin levels and revascularization during wound repair.
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- 2022
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6. NOX2: is the best defense a good offense?
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Zhang, Wen Xuan and Kubes, Paul
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- 2022
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7. NOX2: is the best defense a good offense?
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Zhang, Wen Xuan and Kubes, Paul
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- 2022
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8. Targeting the AnxA1/Fpr2/ALX pathway regulates neutrophil function, promoting thromboinflammation resolution in sickle cell disease
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Ansari, Junaid, Senchenkova, Elena Y., Vital, Shantel A., Al-Yafeai, Zaki, Kaur, Gaganpreet, Sparkenbaugh, Erica M., Orr, A. Wayne, Pawlinski, Rafal, Hebbel, Robert P., Granger, D. Neil, Kubes, Paul, and Gavins, Felicity N. E.
- Abstract
Neutrophils play a crucial role in the intertwined processes of thrombosis and inflammation. An altered neutrophil phenotype may contribute to inadequate resolution, which is known to be a major pathophysiological contributor of thromboinflammatory conditions such as sickle cell disease (SCD). The endogenous protein annexin A1 (AnxA1) facilitates inflammation resolution via formyl peptide receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting the neutrophil-dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of the FPR2/ALX (a fundamental receptor involved in resolution) pathway. We found direct evidence that neutrophils with SCD phenotype play a key role in contributing to thromboinflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal–regulated kinases (ERK1/2) to enable resolution. We present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thromboinflammatory conditions such as SCD.
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- 2021
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9. Targeting the AnxA1/Fpr2/ALX pathway regulates neutrophil function, promoting thromboinflammation resolution in sickle cell disease
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Ansari, Junaid, Senchenkova, Elena Y., Vital, Shantel A., Al-Yafeai, Zaki, Kaur, Gaganpreet, Sparkenbaugh, Erica M., Orr, A. Wayne, Pawlinski, Rafal, Hebbel, Robert P., Granger, D. Neil, Kubes, Paul, and Gavins, Felicity N.E.
- Abstract
Neutrophils play a crucial role in the intertwined processes of thrombosis and inflammation. An altered neutrophil phenotype may contribute to inadequate resolution, which is known to be a major pathophysiological contributor of thromboinflammatory conditions such as sickle cell disease (SCD). The endogenous protein annexin A1 (AnxA1) facilitates inflammation resolution via formyl peptide receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting the neutrophil-dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of the FPR2/ALX (a fundamental receptor involved in resolution) pathway. We found direct evidence that neutrophils with SCD phenotype play a key role in contributing to thromboinflammation. In addition, AnxA1Ac2-26regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal–regulated kinases (ERK1/2) to enable resolution. We present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thromboinflammatory conditions such as SCD.
- Published
- 2021
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10. Patients with COVID-19: in the dark-NETs of neutrophils
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Ackermann, Maximilian, Anders, Hans-Joachim, Bilyy, Rostyslav, Bowlin, Gary L., Daniel, Christoph, De Lorenzo, Rebecca, Egeblad, Mikala, Henneck, Timo, Hidalgo, Andrés, Hoffmann, Markus, Hohberger, Bettina, Kanthi, Yogendra, Kaplan, Mariana J., Knight, Jason S., Knopf, Jasmin, Kolaczkowska, Elzbieta, Kubes, Paul, Leppkes, Moritz, Mahajan, Aparna, Manfredi, Angelo A., Maueröder, Christian, Maugeri, Norma, Mitroulis, Ioannis, Muñoz, Luis E., Narasaraju, Teluguakula, Naschberger, Elisabeth, Neeli, Indira, Ng, Lai Guan, Radic, Marko Z., Ritis, Konstantinos, Rovere-Querini, Patrizia, Schapher, Mirco, Schauer, Christine, Simon, Hans-Uwe, Singh, Jeeshan, Skendros, Panagiotis, Stark, Konstantin, Stürzl, Michael, van der Vlag, Johan, Vandenabeele, Peter, Vitkov, Ljubomir, von Köckritz-Blickwede, Maren, Yanginlar, Cansu, Yousefi, Shida, Zarbock, Alexander, Schett, Georg, and Herrmann, Martin
- Abstract
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
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- 2021
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11. Unraveling the host's immune response to infection: Seeing is believing
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Scott, Brittney N.V., Sarkar, Tina, Kratofil, Rachel M., Kubes, Paul, and Thanabalasuriar, Ajitha
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It has long been appreciated that understanding the interactions between the host and the pathogens that make us sick is critical for the prevention and treatment of disease. As antibiotics become increasingly ineffective, targeting the host and specific bacterial evasion mechanisms are becoming novel therapeutic approaches. The technology used to understand host‐pathogen interactions has dramatically advanced over the last century. We have moved away from using simple in vitro assays focused on single‐cell events to technologies that allow us to observe complex multicellular interactions in real time in live animals. Specifically, intravital microscopy (IVM) has improved our understanding of infection, from viral to bacterial to parasitic, and how the host immune system responds to these infections. Yet, at the same time it has allowed us to appreciate just how complex these interactions are and that current experimental models still have a number of limitations. In this review, we will discuss the advances in vivo IVM has brought to the study of host‐pathogen interactions, focusing primarily on bacterial infections and innate immunity. Reviews the advances in vivo intravital microscopy has brought to the study of host‐pathogen interactions, focusing primarily on bacterial infections and innate immunity.
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- 2019
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12. Neutrophils and NETs in modulating acute and chronic inflammation
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Castanheira, Fernanda V. S. and Kubes, Paul
- Abstract
Neutrophils are an absolutely essential part of the innate immune system, playing an essential role in the control of infectious diseases but more recently are also being viewed as important players in tissue repair. Neutrophils are able to counteract an infection through phagocytosis and/or the release of neutrophil extracellular traps (NETs). By contrast, neutrophils help repair damaged tissues, limiting NET production but still phagocytosing debris. However, when inflammation is recurrent, or the inciting agent persists, neutrophils through a frustrated inability to resolve the problem can release NETs to exacerbate tissue damage during inappropriate inflammation. In this review, we discuss the mechanisms of NET formation, as well as the apparent paradoxical role of neutrophils and NETs in host defense, chronic inflammation, and tissue disrepair.
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- 2019
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13. Neutrophils and NETs in modulating acute and chronic inflammation
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Castanheira, Fernanda V.S. and Kubes, Paul
- Abstract
Neutrophils are an absolutely essential part of the innate immune system, playing an essential role in the control of infectious diseases but more recently are also being viewed as important players in tissue repair. Neutrophils are able to counteract an infection through phagocytosis and/or the release of neutrophil extracellular traps (NETs). By contrast, neutrophils help repair damaged tissues, limiting NET production but still phagocytosing debris. However, when inflammation is recurrent, or the inciting agent persists, neutrophils through a frustrated inability to resolve the problem can release NETs to exacerbate tissue damage during inappropriate inflammation. In this review, we discuss the mechanisms of NET formation, as well as the apparent paradoxical role of neutrophils and NETs in host defense, chronic inflammation, and tissue disrepair.
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- 2019
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14. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
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Malehmir, Mohsen, Pfister, Dominik, Gallage, Suchira, Szydlowska, Marta, Inverso, Donato, Kotsiliti, Elena, Leone, Valentina, Peiseler, Moritz, Surewaard, Bas G. J., Rath, Dominik, Ali, Adnan, Wolf, Monika Julia, Drescher, Hannah, Healy, Marc E., Dauch, Daniel, Kroy, Daniela, Krenkel, Oliver, Kohlhepp, Marlene, Engleitner, Thomas, Olkus, Alexander, Sijmonsma, Tjeerd, Volz, Julia, Deppermann, Carsten, Stegner, David, Helbling, Patrick, Nombela-Arrieta, César, Rafiei, Anahita, Hinterleitner, Martina, Rall, Marcel, Baku, Florian, Borst, Oliver, Wilson, Caroline L., Leslie, Jack, O’Connor, Tracy, Weston, Christopher J., Chauhan, Abhishek, Adams, David H., Sheriff, Lozan, Teijeiro, Ana, Prinz, Marco, Bogeska, Ruzhica, Anstee, Natasha, Bongers, Malte N., Notohamiprodjo, Mike, Geisler, Tobias, Withers, Dominic J., Ware, Jerry, Mann, Derek A., Augustin, Hellmut G., Vegiopoulos, Alexandros, Milsom, Michael D., Rose, Adam J., Lalor, Patricia F., Llovet, Josep M., Pinyol, Roser, Tacke, Frank, Rad, Roland, Matter, Matthias, Djouder, Nabil, Kubes, Paul, Knolle, Percy A., Unger, Kristian, Zender, Lars, Nieswandt, Bernhard, Gawaz, Meinrad, Weber, Achim, and Heikenwalder, Mathias
- Abstract
Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet–immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
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- 2019
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15. To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps
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Boeltz, Sebastian, Amini, Poorya, Anders, Hans-Joachim, Andrade, Felipe, Bilyy, Rostyslav, Chatfield, Simon, Cichon, Iwona, Clancy, Danielle M., Desai, Jyaysi, Dumych, Tetiana, Dwivedi, Nishant, Gordon, Rachael Ann, Hahn, Jonas, Hidalgo, Andrés, Hoffmann, Markus H., Kaplan, Mariana J., Knight, Jason S., Kolaczkowska, Elzbieta, Kubes, Paul, Leppkes, Moritz, Manfredi, Angelo A., Martin, Seamus J., Maueröder, Christian, Maugeri, Norma, Mitroulis, Ioannis, Munoz, Luis E., Nakazawa, Daigo, Neeli, Indira, Nizet, Victor, Pieterse, Elmar, Radic, Marko Z, Reinwald, Christiane, Ritis, Konstantinos, Rovere-Querini, Patrizia, Santocki, Michal, Schauer, Christine, Schett, Georg, Shlomchik, Mark Jay, Simon, Hans-Uwe, Skendros, Panagiotis, Stojkov, Darko, Vandenabeele, Peter, Berghe, Tom Vanden, van der Vlag, Johan, Vitkov, Ljubomir, von Köckritz-Blickwede, Maren, Yousefi, Shida, Zarbock, Alexander, and Herrmann, Martin
- Abstract
Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
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- 2019
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16. Sex-hormone-driven innate antibodies protect females and infants against EPEC infection
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Zeng, Zhutian, Surewaard, Bas G. J., Wong, Connie H. Y., Guettler, Christopher, Petri, Bj?rn, Burkhard, Regula, Wyss, Madeleine, Le Moual, Hervé, Devinney, Rebekah, Thompson, Graham C., Blackwood, Jaime, Joffe, Ari R., McCoy, Kathy D., Jenne, Craig N., and Kubes, Paul
- Abstract
Females have an overall advantage over males in resisting Gram-negative bacteremias, thus hinting at sexual dimorphism of immunity during infections. Here, through intravital microscopy, we observed a sex-biased difference in the capture of blood-borne bacteria by liver macrophages, a process that is critical for the clearance of systemic infections. Complement opsonization was indispensable for the capture of enteropathogenic Escherichia coli(EPEC) in male mice; however, a faster complement component 3–independent process involving abundant preexisting antibodies to EPEC was detected in female mice. These antibodies were elicited predominantly in female mice at puberty in response to estrogen regardless of microbiota-colonization conditions. Estrogen-driven antibodies were maternally transferrable to offspring and conferred protection during infancy. These antibodies were conserved in humans and recognized specialized oligosaccharides integrated into the bacterial lipopolysaccharide and capsule. Thus, an estrogen-driven, innate antibody-mediated immunological strategy conferred protection to females and their offspring.
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- 2018
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17. Innate Immune Cell Trafficking and Function During Sterile Inflammation of the Liver.
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McDonald, Braedon and Kubes, Paul
- Abstract
The sterile inflammatory response (inflammation in the absence of infection) to tissue injury and cell death is required for normal wound healing. However, dysregulated sterile inflammation leads to various acute and chronic inflammatory diseases, including those of the liver and gastrointestinal tract. It is therefore important to increase our understanding of the mechanisms that control physiological versus pathological sterile inflammation. We have begun to clarify the cellular and molecular mechanisms that coordinate the innate immune response to tissue damage and cell death in the liver. In this review, we summarize the mechanisms that alert the immune system to the presence of tissue damage and highlight recent advances in our understanding of innate immune cell trafficking to sites of hepatic sterile inflammation. We explore the functions of various innate immune cells in the coordination of tissue repair, including previously underappreciated roles of peritoneal macrophages and platelets. We propose that dysregulation of immune cell trafficking or function at sites of tissue injury contributes to the misdirection of sterile inflammation to promote chronic inflammatory disease. [ABSTRACT FROM AUTHOR]
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- 2016
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18. Start a fire, kill the bug: The role of platelets in inflammation and infection
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Deppermann, Carsten and Kubes, Paul
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Platelets are the main players in thrombosis and hemostasis; however they also play important roles during inflammation and infection. Through their surface receptors, platelets can directly interact with pathogens and immune cells. Platelets form complexes with neutrophils to modulate their capacities to produce reactive oxygen species or form neutrophil extracellular traps. Furthermore, they release microbicidal factors and cytokines that kill pathogens and influence the immune response, respectively. Platelets also maintain the vascular integrity during inflammation by a mechanism that is different from classical platelet activation. In this review we summarize the current knowledge about how platelets interact with the innate immune system during inflammation and infection and highlight recent advances in the field.
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- 2018
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19. Neutrophil heterogeneity: Bona fide subsets or polarization states?
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Deniset, Justin F. and Kubes, Paul
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Neutrophils are key components of the innate immune system that play important roles during infection, injury, and chronic disease. In recent years, neutrophil heterogeneity has become an emerging focus with accumulating evidence of neutrophil populations with distinct functions under both steady‐state and pathologic conditions. Despite these advances, it remains unclear whether these different populations represent bona fide subsets or simply activation/polarization states in response to local cues. In this review, we summarize the varied neutrophils populations that have been described under both basal and during inflammation. We discuss the evidence that supports the existence of neutrophils subsets. Finally, we identify potential gaps in our knowledge that may further advance our current understanding of neutrophil heterogeneity. Review on neutrophil subsets in both healthy and diseased states.
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- 2018
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20. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system
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Honda, Masaki and Kubes, Paul
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Neutrophil extracellular traps (NETs) have an important role during infection by helping neutrophils to capture and kill pathogens. However, evidence is accumulating that uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. In this Review, we focus on the role of NETs in the liver and gastrointestinal system, outlining their protective and pathological effects. The latest mechanistic insights in NET formation, interactions between microorganisms and NETs and the relationship between neutrophil subtypes and their functions are also discussed. Additionally, we describe the potential importance of NET-related molecules, including cell-free DNA and hypercitrullinated histones, as biomarkers and targets for therapeutic intervention in gastrointestinal diseases.
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- 2018
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21. CRIg Functions as a Macrophage Pattern Recognition Receptor to Directly Bind and Capture Blood-Borne Gram-Positive Bacteria.
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Zeng, Zhutian, Surewaard, Bas G.J., Wong, Connie H.Y., Geoghegan, Joan A., Jenne, Craig N., and Kubes, Paul
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Summary Kupffer cells (KCs), the vast pool of intravascular macrophages in the liver, help to clear blood-borne pathogens. The mechanisms by which KCs capture circulating pathogens remain unknown. Here we use intra-vital imaging of mice infected with Staphylococcus aureus to directly visualize the dynamic process of bacterial capture in the liver. Circulating S . aureus were captured by KCs in a manner dependent on the macrophage complement receptor CRIg, but the process was independent of complement. CRIg bound Staphylococcus aureus specifically through recognition of lipoteichoic acid (LTA), but not cell-wall-anchored surface proteins or peptidoglycan. Blocking the recognition between CRIg and LTA in vivo diminished the bacterial capture in liver and led to systemic bacterial dissemination. All tested Gram-positive, but not Gram-negative, bacteria bound CRIg in a complement-independent manner. These findings reveal a pattern recognition role for CRIg in the direct capture of circulating Gram-positive bacteria from the bloodstream. [ABSTRACT FROM AUTHOR]
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- 2016
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22. Neutrophil Extracellular Traps Provide a Grip on the Enigmatic Pathogenesis of Acute Pancreatitis.
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Korhonen, Juha T., Dudeja, Vikas, Dawra, Rajinder, Kubes, Paul, and Saluja, Ashok
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- 2015
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23. PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury
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Yuan, Qianying, Ren, Chunguang, Xu, Wenwen, Petri, Björn, Zhang, Jiasheng, Zhang, Yong, Kubes, Paul, Wu, Dianqing, and Tang, Wenwen
- Abstract
Polarized vesicle transport plays an important role in cell polarization, but the mechanisms underlying this process and its role in innate immune responses are not well understood. Here, we describe a phosphorylation-regulated polarization mechanism that is important for neutrophil adhesion to endothelial cells during inflammatory responses. We show that the protein kinase PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to guanosine triphosphate (GTP)-bound RAB21. These interactions are important for polarized localization of RAB21 and RPH3A in neutrophils, which leads to PIP5K1C90 polarization. Consistent with the roles of PIP5K1C90 polarization, the lack of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and infiltration in inflammatory models. Furthermore, myeloid-specific loss of PKN1 decreases tissue injury in a renal ischemia-reperfusion model. Thus, this study characterizes a mechanism for protein polarization in neutrophils and identifies a potential protein kinase target for therapeutic intervention in reperfusion-related tissue injury.
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- 2017
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24. Splenic Ly6Ghigh mature and Ly6Gint immature neutrophils contribute to eradication of S. pneumoniae
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Deniset, Justin F., Surewaard, Bas G., Lee, Woo-Yong, and Kubes, Paul
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The spleen plays an integral protective role against encapsulated bacterial infections. Our understanding of the associated mechanisms is limited to thymus-independent (TI) antibody production by the marginal zone (MZ) B cells, leaving the contribution of other splenic compartments such as the red pulp (RP) largely unexplored despite asplenic patients succumbing to the infection in the first 24 h, suggesting important antibody-independent mechanisms. In this study, using time-lapse intravital imaging of the spleen, we identify a tropism for Streptococcus pneumoniae in this organ mediated by tissue-resident MZ and RP macrophages and a protective role for two distinct splenic neutrophil populations (Ly6Ghi and Ly6Gintermediate) residing in the splenic RP. Splenic mature neutrophils mediated pneumococcal clearance in the spleen by plucking bacteria off the surface of RP macrophages that caught the majority of bacteria in a complement-dependent manner. This neutrophil phagocytic capacity was further enhanced after TI antibody production. Resident immature neutrophils (Ly6Gintermediate) in the spleen undergo emergency proliferation and mobilization from their splenic niche after pneumococcal stimulation to increase the effector mature neutrophil pool. We demonstrate that splenic neutrophils together with two macrophage populations and MZ B cells regulate systemic S. pneumoniae clearance through complementary mechanisms.
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- 2017
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25. An emerging role for neutrophil extracellular traps in noninfectious disease
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Jorch, Selina K and Kubes, Paul
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The production of neutrophil extracellular traps (NETs) is a process that enables neutrophils to help catch and kill bacteria. However, increasing evidence suggests that this process might also occur in noninfectious, sterile inflammation. In this Review, we describe the role of NETosis in autoimmunity, coagulation, acute injuries and cancer, and discuss NETs as potential therapeutic targets. Furthermore, we consider whether extracellular DNA is always detrimental in sterile inflammation and whether the source is always NETs.
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- 2017
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26. Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy
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Chen, Jiahuan, Ganguly, Anutosh, Mucsi, Ashley D., Meng, Junchen, Yan, Jiacong, Detampel, Pascal, Munro, Fay, Zhang, Zongde, Wu, Mei, Hari, Aswin, Stenner, Melanie D., Zheng, Wencheng, Kubes, Paul, Xia, Tie, Amrein, Matthias W., Qi, Hai, and Shi, Yan
- Abstract
Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell–DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1–dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin–cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1–dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell–mediated DC suppression in a contact-dependent manner.
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- 2017
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27. Monocyte Conversion During Inflammation and Injury
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Kratofil, Rachel M., Kubes, Paul, and Deniset, Justin F.
- Abstract
Monocytes are circulating leukocytes important in both innate and adaptive immunity, primarily functioning in immune defense, inflammation, and tissue remodeling. There are 2 subsets of monocytes in mice (3 subsets in humans) that are mobilized from the bone marrow and recruited to sites of inflammation, where they carry out their respective functions in promoting inflammation or facilitating tissue repair. Our understanding of the fate of these monocyte subsets at the site of inflammation is constantly evolving. This brief review highlights the plasticity of monocyte subsets and their conversion during inflammation and injury.
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- 2017
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28. Active Negative Pressure Peritoneal Therapy After Abbreviated Laparotomy.
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Kirkpatrick, Andrew W., Roberts, Derek J., Faris, Peter D., Ball, Chad G., Kubes, Paul, Tiruta, Corina, Zhengwen Xiao, Holodinsky, Jessalyn K., McBeth, Paul B., Doig, Christopher J., and Jenne, Craig N.
- Published
- 2015
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29. Intravital Microscopy as a Tool for Studying Recruitment and Chemotaxis.
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Walker, John M., D'Ambrosio, Daniele, Sinigaglia, Francesco, Cara, Denise C., and Kubes, Paul
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Leukocyte recruitment is a hallmark feature of the inflammatory response, which involves a sequential series of molecular interaction between the leukocyte and endothelial cells. First, leukocytes in the mainstream of blood flow come into contact with the endothelium and they roll along the endothelial surface via a group of molecules termed the selectins (1). Next, rolling leukocytes are activated by pro-inflammatory molecules presented on the endothelial surface to firmly adhere to the endothelium via integrins. Once adherent, leukocytes emigrate out of the vasculature and respond to directional (chemotactic) stimuli that guide them to the inflammatory source (2). [ABSTRACT FROM AUTHOR]
- Published
- 2003
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30. iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation
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Thanabalasuriar, Ajitha, Neupane, Arpan S., Wang, Jing, Krummel, Matthew F., and Kubes, Paul
- Abstract
iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against bacterial infections, including S. pneumoniae. Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the specific iNKT cell ligand α-galactosylceramide or S. pneumoniaeinfection. In untreated mice, the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniaeinduced CD1d-dependent rapid recruitment of neutrophils out of the vasculature. The neutrophils guided iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell recruitment by blocking CCL17 increased susceptibility to S. pneumoniaeinfection, suggesting a critical role for the influx of iNKT cells in host defense.
- Published
- 2016
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31. Identification and treatment of the Staphylococcus aureus reservoir in vivo
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Surewaard, Bas G.J., Deniset, Justin F., Zemp, Franz J., Amrein, Matthias, Otto, Michael, Conly, John, Omri, Abdelwahab, Yates, Robin M., and Kubes, Paul
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is reaching epidemic proportions causing morbidity, mortality, and chronic disease due to relapses, suggesting an intracellular reservoir. Using spinning-disk confocal intravital microscopy to track MRSA-GFP in vivo, we identified that within minutes after intravenous infection MRSA is primarily sequestered and killed by intravascular Kupffer cells (KCs) in the liver. However, a minority of the Staphylococci overcome the KC’s antimicrobial defenses. These bacteria survive and proliferate for many days within this intracellular niche, where they remain undetected by recruited neutrophils. Over time, the KCs lyse, releasing bacteria into the circulation, enabling dissemination to other organs such as the kidneys. Vancomycin, the antibiotic of choice to treat MRSA bacteremia, could not penetrate the KCs to eradicate intracellular MRSA. However, based on the intravascular location of these specific macrophages, we designed a liposomal formulation of vancomycin that is efficiently taken up by KCs and diminished the intracellular MRSA. Targeting the source of the reservoir dramatically protected the liver but also dissemination to other organs, and prevented mortality. This vancomycin formulation strategy could help treat patients with Staphylococcal bacteremia without a need for novel antibiotics by targeting the previously inaccessible intracellular reservoir in KCs.
- Published
- 2016
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32. Active Negative Pressure Peritoneal Therapy After Abbreviated Laparotomy
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Kirkpatrick, Andrew W., Roberts, Derek J., Faris, Peter D., Ball, Chad G., Kubes, Paul, Tiruta, Corina, Xiao, Zhengwen, Holodinsky, Jessalyn K., McBeth, Paul B., Doig, Christopher J., and Jenne, Craig N.
- Abstract
Supplemental Digital Content is Available in the Text.This randomized trial observed a survival difference between patients randomized to the ABThera versus Barker's vacuum pack after abbreviated laparotomy. As this difference did not seem to be mediated by improved peritoneal fluid drainage, fascial closure rates, or markers of systemic inflammation, it should be confirmed by a multicenter trial.
- Published
- 2015
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33. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury
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Dal-Secco, Daniela, Wang, Jing, Zeng, Zhutian, Kolaczkowska, Elzbieta, Wong, Connie H.Y., Petri, Björn, Ransohoff, Richard M., Charo, Israel F., Jenne, Craig N., and Kubes, Paul
- Abstract
Monocytes are recruited from the blood to sites of inflammation, where they contribute to wound healing and tissue repair. There are at least two subsets of monocytes: classical or proinflammatory (CCR2hiCX3CR1low) and nonclassical, patrolling, or alternative (CCR2lowCX3CR1hi) monocytes. Using spinning-disk confocal intravital microscopy and mice with fluorescent reporters for each of these subsets, we were able to track the dynamic spectrum of monocytes that enter a site of sterile hepatic injury in vivo. We observed that the CCR2hiCX3CR1low monocytes were recruited early and persisted for at least 48 h, forming a ringlike structure around the injured area. These monocytes transitioned, in situ, from CCR2hiCx3CR1low to CX3CR1hiCCR2low within the ringlike structure and then entered the injury site. This phenotypic conversion was essential for optimal repair. These results demonstrate a local, cytokine driven reprogramming of classic, proinflammatory monocytes into nonclassical or alternative monocytes to facilitate proper wound-healing.
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- 2015
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34. The systemic immune response to trauma: an overview of pathophysiology and treatment
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Lord, Janet M, Midwinter, Mark J, Chen, Yen-Fu, Belli, Antonio, Brohi, Karim, Kovacs, Elizabeth J, Koenderman, Leo, Kubes, Paul, and Lilford, Richard J
- Abstract
Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.
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- 2014
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35. Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: A pilot randomized clinical trial.
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Niven, Daniel J., Stelfox, H. Tom, Léger, Caroline, Kubes, Paul, and Laupland, Kevin B.
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CRITICALLY ill ,FEVER ,PATIENTS ,STATISTICAL sampling ,PILOT projects ,RANDOMIZED controlled trials ,TREATMENT effectiveness ,DISEASE incidence ,DESCRIPTIVE statistics ,NONOPIOID analgesics ,PHARMACODYNAMICS - Published
- 2013
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36. Neutrophils Recruited to Sites of Infection Protect from Virus Challenge by Releasing Neutrophil Extracellular Traps.
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Jenne, Craig N., Wong, Connie H.Y., Zemp, Franz J., McDonald, Braedon, Rahman, Masmudur M., Forsyth, Peter A., McFadden, Grant, and Kubes, Paul
- Subjects
NEUTROPHIL immunology ,BIOCHEMICAL mechanism of action ,DNA structure ,VIRUS diseases ,ANTIVIRAL agents ,NATURAL immunity ,POXVIRUS diseases ,LIVER blood-vessels - Abstract
Summary: Neutrophils mediate bacterial clearance through various mechanisms, including the release of mesh-like DNA structures or neutrophil extracellular traps (NETs) that capture bacteria. Although neutrophils are also recruited to sites of viral infection, their role in antiviral innate immunity is less clear. We show that systemic administration of virus analogs or poxvirus infection induces neutrophil recruitment to the liver microvasculature and the release of NETs that protect host cells from virus infection. After systemic intravenous poxvirus challenge, mice exhibit thrombocytopenia and the recruitment of both neutrophils and platelets to the liver vasculature. Circulating platelets interact with, roll along, and adhere to the surface of adherent neutrophils, forming large, dynamic aggregates. These interactions facilitate the release of NETs within the liver vasculature that are able to protect host cells from poxvirus infection. These findings highlight the role of NETs and early tissue-wide responses in preventing viral infection. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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37. Sterile Inflammation in the Liver.
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Kubes, Paul and Mehal, Wajahat Z.
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HEPATITIS ,PATHOGENIC microorganisms ,TISSUE wounds ,FATTY liver ,IMMUNE response ,TOLL-like receptors ,CELLULAR signal transduction - Abstract
Inflammation In the absence of pathogens occurs in all tissues in response to a wide range of stimuli that cause tissue stress and injury. Such sterile inflammation (SI) is a key process in drug-induced liver injury, nonalcoholic steatohepatitis, and alcoholic steatohepatitis and is a major determinant of fibrosis and carcinogenesis. In SI, endogenous damage-associated molecular patterns (DAMPS), which are usually hidden from the extracellular environment, are released on tissue injury and activate receptors on immune cells. More than 20 such DAMPS have been identified and activate cellular pattern recognition receptors, which were originally identified as sensors of pathogen-associated molecular patterns. Activation of pattern recognition receptors by DAMPS results in a wide range of immune responses, including production of proinflammatory cytokines and localization of immune cells to the site of injury. DAMPS result in the assembly of a cytosolic protein complex termed the inflammasome, which activates the serine protease caspase-1, resulting in activation and secretion of interleukin-1β and other cytokines. SI-driven liver diseases are responsible for the majority of liver pathology in industrially developed countries and lack specific therapy. Identification of DAMPS, their receptors, signaling pathways, and cytokines now provides a wide range of therapeutic targets for which many antagonists are already available. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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38. Intravascular Neutrophil Extracellular Traps Capture Bacteria from the Bloodstream during Sepsis.
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McDonald, Braedon, Urrutia, Rossana, Yipp, Bryan G., Jenne, Craig N., and Kubes, Paul
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NEUTROPHILS ,SEPSIS ,EXTRACELLULAR matrix ,INFLAMMATION ,ENDOTOXEMIA ,IMMUNE response ,BLOOD platelets - Abstract
Summary: During the systemic inflammatory response of severe sepsis, neutrophils accumulate in the liver microcirculation, but their functional significance is largely unknown. We show that neutrophils migrate to liver sinusoids during endotoxemia and sepsis where they exert protective effects by releasing neutrophil extracellular traps (NETs), which are DNA-based structures that capture and eliminate microbes. NETs released into the vasculature ensnare bacteria from the bloodstream and prevent dissemination. NET production requires platelet-neutrophil interactions and can be inhibited by platelet depletion or disruption of integrin-mediated platelet-neutrophil binding. During sepsis, NET release increases bacterial trapping by 4-fold (beyond the basal level provided by resident intravascular macrophages). Blocking NET formation reduces the capture of circulating bacteria during sepsis, resulting in increased dissemination to distant organs. Thus, NETs ensnare circulating bacteria and provide intravascular immunity that protects against bacterial dissemination during septic infections. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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39. Modulating leukocyte recruitment in inflammation.
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Kelly, Margaret, Hwang, John M., and Kubes, Paul
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OBSTRUCTIVE lung diseases ,LUNG disease diagnosis ,BRONCHOALVEOLAR lavage ,INFLAMMATION ,LEUCOCYTES - Abstract
Much information has been obtained regarding how white cells are recruited in the microcirculation to sites of inflammation. In this review we summarize the leukocyte recruitment cascade, highlighting the molecular mechanisms that underlie each of the major steps. Major emphasis is placed on the selectins and integrins and their role in rolling and adhesion. Intraluminal crawling and emigration are also briefly discussed. In addition, we summarize some of the data that implicate these molecules in eosinophil recruitment in animal models of asthma and in lymphocyte recruitment in skin contact sensitivity. There is a growing body of evidence to suggest that leukocyte recruitment could be used as an effective means for future therapeutics, and some of these issues are also raised. [Copyright &y& Elsevier]
- Published
- 2007
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40. Neutrophil phenotypes and functions in cancer: A consensus statement
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Quail, Daniela F., Amulic, Borko, Aziz, Monowar, Barnes, Betsy J., Eruslanov, Evgeniy, Fridlender, Zvi G., Goodridge, Helen S., Granot, Zvi, Hidalgo, Andrés, Huttenlocher, Anna, Kaplan, Mariana J., Malanchi, Ilaria, Merghoub, Taha, Meylan, Etienne, Mittal, Vivek, Pittet, Mikael J., Rubio-Ponce, Andrea, Udalova, Irina A., van den Berg, Timo K., Wagner, Denisa D., Wang, Ping, Zychlinsky, Arturo, de Visser, Karin E., Egeblad, Mikala, and Kubes, Paul
- Abstract
Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer.
- Published
- 2022
- Full Text
- View/download PDF
41. Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow
- Author
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Devi, Sapna, Wang, Yilin, Chew, Weng Keong, Lima, Ronald, A-González, Noelia, Mattar, Citra N.Z., Chong, Shu Zhen, Schlitzer, Andreas, Bakocevic, Nadja, Chew, Samantha, Keeble, Jo L., Goh, Chi Ching, Li, Jackson L.Y., Evrard, Maximilien, Malleret, Benoit, Larbi, Anis, Renia, Laurent, Haniffa, Muzlifah, Tan, Suet Mien, Chan, Jerry K.Y., Balabanian, Karl, Nagasawa, Takashi, Bachelerie, Françoise, Hidalgo, Andrés, Ginhoux, Florent, Kubes, Paul, and Ng, Lai Guan
- Abstract
Blood neutrophil homeostasis is essential for successful host defense against invading pathogens. Circulating neutrophil counts are positively regulated by CXCR2 signaling and negatively regulated by the CXCR4–CXCL12 axis. In particular, G-CSF, a known CXCR2 signaler, and plerixafor, a CXCR4 antagonist, have both been shown to correct neutropenia in human patients. G-CSF directly induces neutrophil mobilization from the bone marrow (BM) into the blood, but the mechanisms underlying plerixafor-induced neutrophilia remain poorly defined. Using a combination of intravital multiphoton microscopy, genetically modified mice and novel in vivo homing assays, we demonstrate that G-CSF and plerixafor work through distinct mechanisms. In contrast to G-CSF, CXCR4 inhibition via plerixafor does not result in neutrophil mobilization from the BM. Instead, plerixafor augments the frequency of circulating neutrophils through their release from the marginated pool present in the lung, while simultaneously preventing neutrophil return to the BM. Our study demonstrates for the first time that drastic changes in blood neutrophils can originate from alternative reservoirs other than the BM, while implicating a role for CXCR4–CXCL12 interactions in regulating lung neutrophil margination. Collectively, our data provides valuable insights into the fundamental regulation of neutrophil homeostasis, which may lead to the development of improved treatment regimens for neutropenic patients.
- Published
- 2013
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42. NETosis: how vital is it?
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Yipp, Bryan G. and Kubes, Paul
- Abstract
In this review, we examine the evidence that neutrophil extracellular traps (NETs) play a critical role in innate immunity. We summarize how NETs are formed in response to various stimuli and provide evidence that NETosis is not universally a cell death pathway. Here we describe at least 2 different mechanisms by which NETs are formed, including a suicide lytic NETosis and a live cell or vital NETosis. We also evaluate the evidence for NETs in catching and killing pathogens. Finally, we examine how infections are related to the development of autoimmune and vasculitic diseases through unintended but detrimental bystander damage resulting from NET release.
- Published
- 2013
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- View/download PDF
43. NETosis: how vital is it?
- Author
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Yipp, Bryan G. and Kubes, Paul
- Abstract
In this review, we examine the evidence that neutrophil extracellular traps (NETs) play a critical role in innate immunity. We summarize how NETs are formed in response to various stimuli and provide evidence that NETosis is not universally a cell death pathway. Here we describe at least 2 different mechanisms by which NETs are formed, including a suicide lytic NETosis and a live cell or vital NETosis. We also evaluate the evidence for NETs in catching and killing pathogens. Finally, we examine how infections are related to the development of autoimmune and vasculitic diseases through unintended but detrimental bystander damage resulting from NET release.
- Published
- 2013
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44. Panning for brain antigens in dural sinuses
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Bogoslowski, Ania and Kubes, Paul
- Published
- 2021
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45. Author Correction: Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
- Author
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Malehmir, Mohsen, Pfister, Dominik, Gallage, Suchira, Szydlowska, Marta, Inverso, Donato, Kotsiliti, Elena, Leone, Valentina, Peiseler, Moritz, Surewaard, Bas G. J., Rath, Dominik, Ali, Adnan, Wolf, Monika Julia, Drescher, Hannah, Healy, Marc E., Dauch, Daniel, Kroy, Daniela, Krenkel, Oliver, Kohlhepp, Marlene, Engleitner, Thomas, Olkus, Alexander, Sijmonsma, Tjeerd, Volz, Julia, Deppermann, Carsten, Stegner, David, Helbling, Patrick, Nombela-Arrieta, César, Rafiei, Anahita, Hinterleitner, Martina, Rall, Marcel, Baku, Florian, Borst, Oliver, Wilson, Caroline L., Leslie, Jack, O’Connor, Tracy, Weston, Christopher J., Chauhan, Abhishek, Adams, David H., Sheriff, Lozan, Teijeiro, Ana, Prinz, Marco, Bogeska, Ruzhica, Anstee, Natasha, Bongers, Malte N., Notohamiprodjo, Mike, Geisler, Tobias, Withers, Dominic J., Ware, Jerry, Mann, Derek A., Augustin, Hellmut G., Vegiopoulos, Alexandros, Milsom, Michael D., Rose, Adam J., Lalor, Patricia F., Llovet, Josep M., Pinyol, Roser, Tacke, Frank, Rad, Roland, Matter, Matthias, Djouder, Nabil, Kubes, Paul, Knolle, Percy A., Unger, Kristian, Zender, Lars, Nieswandt, Bernhard, Gawaz, Meinrad, Weber, Achim, and Heikenwalder, Mathias
- Published
- 2022
- Full Text
- View/download PDF
46. Damage-Associated Molecular Patterns Control Neutrophil Recruitment
- Author
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Pittman, Keir and Kubes, Paul
- Abstract
AbstractNeutrophils are recruited to a site of infection or injury where they help initiate the acute inflammatory response. In instances of sterile inflammation, where no microbial threats are present, this neutrophil recruitment is mediated by the release of danger signals or damage-associated molecular patterns (DAMPs) from disrupted cells and tissues. At basal state, many of these substances are sequestered and remain hidden within the cell, but are released following the rupture of the plasma membrane. In other instances, these DAMPs are undetected by the innate immune system unless chemically or proteolytically modified by tissue damage. DAMPs may be directly detected by neutrophils themselves and modulate their recruitment to sites of damage or, alternatively, they can act on other cell types which in turn facilitate the arrival of neutrophils to a site of injury. In this review, we outline the direct and indirect effects of a number of DAMPs, notably extracellular ATP, mitochondrial formylated peptides and mitochondrial DNA, all of which are released by necrotic cells. We examine the effect of these substances on the recruitment and behaviour of neutrophils to sites of sterile injury. We also highlight research which suggests that neutrophils are actively involved in triggering the resolution phase of an inflammatory response. This review brings to light a growing body of work that demonstrates that the release of DAMPs and the ensuing influx of neutrophils plays an important functional role in the inflammatory response, even when no pathogens are present.Copyright © 2013 S. Karger AG, Basel
- Published
- 2013
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47. Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo
- Author
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Petri, Björn, Kaur, Jaswinder, Long, Elizabeth M., Li, Hang, Parsons, Sean A., Butz, Stefan, Phillipson, Mia, Vestweber, Dietmar, Patel, Kamala D., Robbins, Stephen M., and Kubes, Paul
- Abstract
The endothelium actively participates in neutrophil migration out of the vasculature via dynamic, cytoskeleton-dependent rearrangements leading to the formation of transmigratory cups in vitro, and to domes that completely surround the leukocyte in vivo. Leukocyte-specific protein 1 (LSP1), an F-actin–binding protein recently shown to be in the endothelium, is critical for effective transmigration, although the mechanism has remained elusive. Herein we show that endothelial LSP1 is expressed in the nucleus and cytosol of resting endothelial cells and associates with the cytoskeleton upon endothelial activation. Two-photon microscopy revealed that endothelial LSP1 was crucial for the formation of endothelial domes in vivo in response to neutrophil chemokine keratinocyte-derived chemokine (KC) as well as in response to endogenously produced chemokines stimulated by cytokines (tumor necrosis factor a [TNFa] or interleukin-1ß [IL-1ß]). Endothelial domes were significantly reduced in Lsp1-/- compared with wild-type (WT) mice. Lsp1-/- animals not only showed impaired neutrophil emigration after KC and TNFa stimulation, but also had disproportionate increases in vascular permeability. We demonstrate that endothelial LSP1 is recruited to the cytoskeleton in inflammation and plays an important role in forming endothelial domes thereby regulating neutrophil transendothelial migration. The permeability data may underscore the physiologic relevance of domes and the role for LSP1 in endothelial barrier integrity.
- Published
- 2011
- Full Text
- View/download PDF
48. Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo
- Author
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Petri, Björn, Kaur, Jaswinder, Long, Elizabeth M., Li, Hang, Parsons, Sean A., Butz, Stefan, Phillipson, Mia, Vestweber, Dietmar, Patel, Kamala D., Robbins, Stephen M., and Kubes, Paul
- Abstract
The endothelium actively participates in neutrophil migration out of the vasculature via dynamic, cytoskeleton-dependent rearrangements leading to the formation of transmigratory cups in vitro, and to domes that completely surround the leukocyte in vivo. Leukocyte-specific protein 1 (LSP1), an F-actin–binding protein recently shown to be in the endothelium, is critical for effective transmigration, although the mechanism has remained elusive. Herein we show that endothelial LSP1 is expressed in the nucleus and cytosol of resting endothelial cells and associates with the cytoskeleton upon endothelial activation. Two-photon microscopy revealed that endothelial LSP1 was crucial for the formation of endothelial domes in vivo in response to neutrophil chemokine keratinocyte-derived chemokine (KC) as well as in response to endogenously produced chemokines stimulated by cytokines (tumor necrosis factor α [TNFα] or interleukin-1β [IL-1β]). Endothelial domes were significantly reduced in Lsp1−/−compared with wild-type (WT) mice. Lsp1−/−animals not only showed impaired neutrophil emigration after KC and TNFα stimulation, but also had disproportionate increases in vascular permeability. We demonstrate that endothelial LSP1 is recruited to the cytoskeleton in inflammation and plays an important role in forming endothelial domes thereby regulating neutrophil transendothelial migration. The permeability data may underscore the physiologic relevance of domes and the role for LSP1 in endothelial barrier integrity.
- Published
- 2011
- Full Text
- View/download PDF
49. Mast Cells Regulate the Magnitude and the Cytokine Microenvironment of the Contact Hypersensitivity Response
- Author
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Norman, M. Ursula, Hwang, John, Hulliger, Sara, Bonder, Claudine S., Yamanouchi, Jun, Santamaria, Pere, and Kubes, Paul
- Abstract
The role that mast cells play during contact hypersensitivity (CS) response is unclear because some studies have shown that mast cell-deficient mice have relatively intact CS responses whereas others have shown opposing results. Mast cells secrete a wide range of immunomodulatory mediators and can potentially influence the type of immune response generated in the skin during CS. Therefore, we examined the type of microenvironment generated during CS in both W/Wv mast cell-deficient and wild-type mice in response to different immunizing doses of hapten (oxazolone). The CS response elicited after low-dose oxazolone was significantly diminished in W/Wv mice compared with wild-type mice. Unexpectedly, the CS response elicited in W/Wv mice immunized with high-dose oxazolone was more severe compared with wild-type mice. In addition, after immunization with high-dose oxazolone, the granulocyte infiltrate in W/Wv mice was increased by twofold compared with wild-type mice. A shift in the cytokine milieu toward the expression of type-1 cytokines as well as a significant increase in the local adhesion of neutrophils and CD4 T cells in the microvasculature of the skin was observed after hapten challenge in W/Wv mice immunized with high-dose oxazolone compared with wild-type mice. These results suggest that mast cells can act as regulators and inducers of the inflammatory response depending on immunizing stimulus strength.
- Published
- 2008
- Full Text
- View/download PDF
50. Leukocyte PI3Kγ and PI3Kδ have temporally distinct roles for leukocyte recruitment in vivo
- Author
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Liu, Lixin, Puri, Kamal D., Penninger, Josef M., and Kubes, Paul
- Abstract
Phosphoinositide 3-kinases (PI3Ks) have been considered important in leukocyte motility. PI3Kγ, the class IBPI3K, expressed prominently in leukocytes and also in endothelial cells, mediates leukocyte functional responses induced by chemoattractants. To reveal its role in leukocyte recruitment, we used intravital microscopy to directly visualize leukocyte rolling, adhesion, and emigration in postcapillary venules in PI3Kγ-deficient (PI3Kγ-/-)mice. We report here that PI3Kγ deficiency had no significant effects on leukocyte rolling flux or rolling velocity and minor effects on adhesion (30% to 35%) in response to CXC chemokine MIP-2 (CXCL2) or KC (CXCL1). However, leukocyte emigration was severely impaired in PI3Kγ-/-mice in an early (first 90 minutes) response to MIP-2 or KC. Chimeric mice receiving bone marrow transplants revealed that this early response was entirely dependent upon PI3Kγ in neutrophils but not parenchymal cells (endothelium and others). Identical responses were observed when endogenous chemokine production was induced by TNFα; leukocyte emigration was reduced in PI3Kγ-/-mice. More prolonged responses to MIP-2 (for 4 to 5 hours) or TNFα (6 to 8 hours) were almost entirely PI3Kγ independent and largely dependent on PI3Kδ. Our results reveal that leukocyte emigration response to CXC chemokines is entirely dependent upon PI3Kγ or PI3Kδ, but these are nonoverlapping, temporally distinct events in inflamed tissues in vivo.
- Published
- 2007
- Full Text
- View/download PDF
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