Immune surveillance by the liver Jenne, Craig N; Kubes, Paul
Nature immunology,
10/2013, Letnik:
14, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Receiving both portal vein blood and arterial blood, the liver is an important and critical component in the defense against blood-borne infection. To accomplish this role, the liver contains ...numerous innate and adaptive immune cells that specialize in detection and capture of pathogens from the blood. Further, these immune cells participate in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes within the vasculature. Finally, this role in host defense must be tightly regulated to ensure that inappropriate immune responses are not raised against nonpathogenic exogenous blood-borne molecules, such as those derived from food. It is this balance between activation and tolerance that characterizes the liver as a frontline immunological organ.
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.
► Neutrophils release intravascular NETs in liver sinusoids during endotoxemia/sepsis ► Production of NETs requires integrin-dependent interactions with platelets ► Intravascular NETs capture circulating bacteria 4× better than Kupffer cells alone ► Intravascular NETs protect against bacterial dissemination during sepsis
Despite their small size and anucleate status, platelets have diverse roles in vascular biology. Not only are platelets the cellular mediator of thrombosis, but platelets are also immune cells that ...initiate and accelerate many vascular inflammatory conditions. Platelets are linked to the pathogenesis of inflammatory diseases such as atherosclerosis, malaria infection, transplant rejection, and rheumatoid arthritis. In some contexts, platelet immune functions are protective, whereas in others platelets contribute to adverse inflammatory outcomes. In this review, we will discuss platelet and platelet-derived mediator interactions with the innate and acquired arms of the immune system and platelet-vessel wall interactions that drive inflammatory disease. There have been many recent publications indicating both important protective and adverse roles for platelets in infectious disease. Because of this new accumulating data, and the fact that infectious disease continues to be a leading cause of death globally, we will also focus on new and emerging concepts related to platelet immune and inflammatory functions in the context of infectious disease.
Neutrophil extracellular traps (NETs; webs of DNA coated in antimicrobial proteins) are released into the vasculature during sepsis where they contribute to host defense, but also cause tissue damage ...and organ dysfunction. Various components of NETs have also been implicated as activators of coagulation. Using multicolor confocal intravital microscopy in mouse models of sepsis, we observed profound platelet aggregation, thrombin activation, and fibrin clot formation within (and downstream of) NETs in vivo. NETs were critical for the development of sepsis-induced intravascular coagulation regardless of the inciting bacterial stimulus (gram-negative, gram-positive, or bacterial products). Removal of NETs via DNase infusion, or in peptidylarginine deiminase-4–deficient mice (which have impaired NET production), resulted in significantly lower quantities of intravascular thrombin activity, reduced platelet aggregation, and improved microvascular perfusion. NET-induced intravascular coagulation was dependent on a collaborative interaction between histone H4 in NETs, platelets, and the release of inorganic polyphosphate. Real-time perfusion imaging revealed markedly improved microvascular perfusion in response to the blockade of NET-induced coagulation, which correlated with reduced markers of systemic intravascular coagulation and end-organ damage in septic mice. Together, these data demonstrate, for the first time in an in vivo model of infection, a dynamic NET–platelet–thrombin axis that promotes intravascular coagulation and microvascular dysfunction in sepsis.
•In vivo imaging reveals a NET–platelet–thrombin axis that promotes intravascular coagulation in sepsis.•Inhibition of NETs during sepsis reduces intravascular coagulation, improves microvascular perfusion, and reduces organ damage.
Abstract
Although platelets are traditionally recognized for their central role in hemostasis, many lines of research clearly demonstrate these rather ubiquitous blood components are potent immune ...modulators and effectors. Platelets have been shown to directly recognize, sequester and kill pathogens, to activated and recruit leukocytes to sites of infection and inflammation, and to modulate leukocyte behavior, enhancing their ability to phagocytose and kill pathogens and inducing unique effector functions, such as the production of Neutrophil Extracellular Traps (NETs). This multifaceted response to infection and inflammation is due, in part, to the huge array of soluble mediators and cell surface molecules expressed by platelets. From their earliest origins as primordial hemocytes in invertebrates to their current form as megakaryocyte-derived cytoplasts, platelets have evolved to be one of the key regulators of host intravascular immunity and inflammation. In this review, we present the diverse roles platelets play in immunity and inflammation associated with autoimmune diseases and infection. Additionally, we highlight recent advances in our understanding of platelet behavior made possible through the use of advanced imaging techniques that allow us to visualize platelets and their interactions, in real-time, within the intact blood vessels of a living host.
Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received significant research attention for ...>150 years. The immune cell functions of platelets are much less appreciated. Platelets interact with and activate cells of all branches of immunity in response to pathogen exposures and infection, as well as in response to sterile tissue injury. In this review, we focus on innate immune mechanisms of platelet activation, platelet interactions with innate immune cells, as well as the intersection of platelets and adaptive immunity. The immune potential of platelets is dependent in part on their megakaryocyte precursor providing them with the molecular composition to be first responders and immune sentinels in initiating and orchestrating coordinated pathogen immune responses. There is emerging evidence that extramedullary megakaryocytes may be immune differentiated compared with bone marrow megakaryocytes, but the physiological relevance of immunophenotypic differences are just beginning to be explored. These concepts are also discussed in this review. The immune functions of the megakaryocyte/platelet lineage have likely evolved to coordinate the need to repair a vascular breach with the simultaneous need to induce an immune response that may limit pathogen invasion once the blood is exposed to an external environment.
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.
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•Kupffer cells (KCs) capture circulating S. aureus in the liver•Macrophage receptor CRIg, but not complement, is required for pathogen capture by KCs•CRIg directly binds Gram-positive bacteria via lipoteichoic acid (LTA) recognition•CRIg-LTA recognition is required for clearance of circulating Gram-positive bacteria
Liver macrophages called Kupffer cells (KCs) capture circulating pathogens. Using intravital imaging to visualize bacterial capture by KCs, Zeng et al. discover that CRIg functions as a pattern recognition receptor on KCs to directly bind Gram-positive bacteria via lipoteichoic acid (LTA). CRIg-LTA recognition is required for clearance of circulating bacteria.
ABSTRACT
Currently on the rise in archaeology, ontological approaches promise new ways of engaging with alterity of various kinds—different people, different times, different forms, even different ...worlds. This work promises to aid in critical reflections on the arbitrary nature of the Western gaze and to recognize and incorporate non‐Western knowledge in new manners. There are, however, several challenges to address. First, as noted by several leading thinkers in this area, the present range of ontological approaches include contrasting theoretical underpinnings. Second, these approaches are rarely considered in relation to the practical challenges of specific archaeological cases, particularly contexts of settler colonialism in which practitioners are attuned to the potential colonial nature of their work. I divide ontologically engaged archaeologies into three related but distinct groups and use a small museum assemblage of seventeenth‐century Wendat materials from Ontario to help think through these three theories. In comparing approaches, I outline their respective strengths, weaknesses, and points in need of further clarification. I conclude that the ontological turns offer new and valuable angles of articulation with archaeological materials but that archaeologists must adopt them cautiously if they are to avoid repeating or continuing some of the darkest parts of our (colonial) disciplinary history. ontology, archaeology, new materialism, archaeological theory, effigies, colonialism, Iroquoian archaeology, Ontario
RESUMEN
Actualmente se están desarrollando en la arqueología, aproximaciones ontológicas que prometen nuevas formas de comprometerse con la alteridad de varios tipos—personas diferentes, tiempos diferentes, formas diferentes, aun mundos diferentes. Este trabajo promete ayudar en reflexiones críticas sobre la naturaleza arbitraria de la mirada occidental y para reconocer e incorporar conocimiento no occidental en nuevas formas. Hay, sin embargo, varios retos para abordar. Primero, como señalado por varios pensadores destacados en esta área, el rango actual de aproximaciones ontológicas incluye fundamentos teóricos contrastantes. Segundo, estas aproximaciones son consideradas raramente en relación con los retos prácticos de casos arqueológicos específicos, particularmente los contextos del colonialismo de pobladores en los cuales los profesionales están sintonizados con la naturaleza colonial potencial de su trabajo. Divido las arqueologías comprometidas ontológicamente en tres grupos relacionados pero distintos y uso un ensamblaje pequeño de museo de materiales de los hurones del siglo XVII de Ontario para ayudar a pensar a través de estas tres teorías. Comparando las aproximaciones, bosquejo sus debilidades, fortalezas respectivas, y puntos en necesidad de clarificación adicional. Concluyo que los cambios ontológicos ofrecen ángulos de articulación nuevos y valiosos con materiales arqueológicos, pero que los arqueólogos los deben adoptar con cautela si van a evitar repetir o continuar algunas de las partes más oscuras de nuestra historia disciplinaria (colonial). ontología, arqueología, materialismo nuevo, teoría arqueológica, efigies, colonialismo, arqueología Iroquesa, Ontario
RÉSUMÉ
Les démarches ontologiques offrent un cadre théorique prometteur pour l’étude de l'altérité. Elles permettent une réflexion critique sur la nature arbitraire du regard occidental et reconnaissent les savoirs non occidentaux. Il y a toutefois plusieurs défis à relever. D'abord, les approches ontologiques se basent souvent sur des assises théoriques contradictoires. Ensuite, elles prennent rarement en compte les défis pratiques associés à des cas spécifiques, comme les recherches en contexte colonial où le risque de renforcer une vision colonialiste est réel. J'utilise une collection muséologique d'objets wendats de l'Ontario du XVIIe siècle afin de comparer trois approches ontologiques utilisées en archéologie. Je souligne ainsi leurs forces et leurs faiblesses, en plus de mettre en évidence certains points nécessitant une plus grande clarification. Le tournant ontologique offre des cadres théoriques prometteurs, mais les archéologues doivent les adopter de façon critique afin d’éviter la répétition de moments sombres de l'histoire de notre discipline. ontologie, archéologie, nouveau matérialisme, théorie archéologique, effigies, colonialisme, archéologie iroquoienne, Ontario
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.
► Systemic virus challenge induces neutrophil and platelet recruitment to the liver ► Platelets bind adherent neutrophils, generating large dynamic aggregates ► Viral infection induces the release of NETs within the liver microvasculature ► NETs can protect host cells from viral infection in vivo
The Tasman Sea off southeast Australia exhibited its longest and most intense marine heatwave ever recorded in 2015/16. Here we report on several inter-related aspects of this event: observed ...characteristics, physical drivers, ecological impacts and the role of climate change. This marine heatwave lasted for 251 days reaching a maximum intensity of 2.9 °C above climatology. The anomalous warming is dominated by anomalous convergence of heat linked to the southward flowing East Australian Current. Ecosystem impacts range from new disease outbreaks in farmed shellfish, mortality of wild molluscs and out-of-range species observations. Global climate models indicate it is very likely to be that the occurrence of an extreme warming event of this duration or intensity in this region is respectively ≥330 times and ≥6.8 times as likely to be due to the influence of anthropogenic climate change. Climate projections indicate that event likelihoods will increase in the future, due to increasing anthropogenic influences.
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