Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis

The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.     

Bench-to-bedside review: Toll-like receptors and their role in septic shock

The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader. The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host–pathogen interactions. These functional attributes of the cellular receptors provide insights into the nature of pattern recognition receptors that activate the human antimicrobial defense systems. The fundamental significance of the TLRs in the generation of systemic inflammation and the pathogenesis of septic shock is reviewed. The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.     

Mannose-binding lectin and the balance between immune protection and complication

The innate immune system is evolutionarily ancient and biologically primitive. Historically, it was first identified as an element of the immune system that provides the first-line response to pathogens, and increasingly it is recognized for its central housekeeping role and its essential functions in tissue homeostasis, including coagulation and inflammation, among others. A pivotal link between the innate immune system and other functions is mannose-binding lectin (MBL), a pattern recognition molecule. Multiple studies have demonstrated that MBL deficiency increases susceptibility to infection, and the mechanisms associated with this susceptibility to infection include reduced opsonophagocytic killing and reduced activation of the lectin complement pathway. Results from our laboratory have demonstrated that MBL and MBL-associated serine protease (MASP)-1/3 together mediate coagulation factor-like activities, including thrombin-like activity. MBL and/or MASP-1/3-deficient hosts demonstrate in vivo evidence that MBL and MASP-1/3 are involved with hemostasis following injury. Staphylococcus aureus-infected MBL null mice developed disseminated intravascular coagulation, which was associated with elevated blood IL-6 levels (but not TNF-α) and systemic inflammatory responses. Infected MBL null mice also develop liver injury. These findings suggest that MBL deficiency may manifest as disseminated intravascular coagulation and organ failure with infection. Beginning from these observations, this review focuses on the interaction of innate immunity and other homeostatic systems, the derangement of which may lead to complications in infection and other inflammatory states.     

Mannose-binding lectin and the balance between immune protection and complication

The innate immune system is evolutionarily ancient and biologically primitive. Historically, it was first identified as an element of the immune system that provides the first-line response to pathogens, and increasingly it is recognized for its central housekeeping role and its essential functions in tissue homeostasis, including coagulation and inflammation, among others. A pivotal link between the innate immune system and other functions is mannose-binding lectin (MBL), a pattern recognition molecule. Multiple studies have demonstrated that MBL deficiency increases susceptibility to infection, and the mechanisms associated with this susceptibility to infection include reduced opsonophagocytic killing and reduced activation of the lectin complement pathway. Results from our laboratory have demonstrated that MBL and MBL-associated serine protease (MASP)-1/3 together mediate coagulation factor-like activities, including thrombin-like activity. MBL and/or MASP-1/3-deficient hosts demonstrate in vivo evidence that MBL and MASP-1/3 are involved with hemostasis following injury. Staphylococcus aureus-infected MBL null mice developed disseminated intravascular coagulation, which was associated with elevated blood IL-6 levels (but not TNF-α) and systemic inflammatory responses. Infected MBL null mice also develop liver injury. These findings suggest that MBL deficiency may manifest as disseminated intravascular coagulation and organ failure with infection. Beginning from these observations, this review focuses on the interaction of innate immunity and other homeostatic systems, the derangement of which may lead to complications in infection and other inflammatory states.     

Immunomodulation and sepsis: impact of the pathogen

Infection begins when microorganisms overcome host barriers and multiply within host tissues. To contain the infection, the host mounts an inflammatory response that mobilizes defense systems and kills the invading microorganisms. A focal inflammatory response is usually sufficient to eradicate the organisms. However, when it fails to contain the infection, the organisms, their toxins, and numerous host mediators are released into the bloodstream, producing a systemic inflammatory response and organ failure. Microorganisms have coevolved with their hosts, thereby acquiring means of overcoming host defense mechanisms or even taking advantage of innate host responses. Many pathogens avoid recognition by the host or dampen host immune responses via sophisticated pathogen-host interactions. Some pathogens benefit from the inflammatory response. According to current hypotheses regarding the pathogenesis of sepsis, the host generates both an innate immune response identical for all pathogens and an adaptive pathogen-specific response. Determining whether the innate response benefits the pathogen or the host is essential for understanding host-pathogen interactions. In this review, we discuss how pathogens interfere with innate and adaptive immune responses to escape eradication by the host.     

Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome

Innate immunity is the first-line defense against pathogens and relies on phagocytes, soluble components, and cell-surface and cytosolic pattern recognition receptors. Despite using hard-wired receptors and signaling pathways, the innate immune response demonstrates surprising specificity to different pathogens. We determined how combinatorial use of innate immune defense mechanisms defines the response. We describe a novel cooperation between a soluble component of the innate immune system, the mannose-binding lectin, and Toll-like receptor 2 that both specifies and amplifies the host response to Staphylococcus aureus. Furthermore, we demonstrate that this cooperation occurs within the phagosome, emphasizing the importance of engulfment in providing the appropriate cellular environment to facilitate the synergy between these defense pathways.     

Coagulation, inflammation and immune response -- an evolutionary conserved plan as cause for disseminated intravasal coagulation?

The concomitant activation of the immune response and the coagulation system in response to injury represents a phylogenetic old and adaptive principle already present in the early eukaryotic development. The close connection between coagulation, inflammation, and immune defense has been conserved during evolution and can still be found in humans in a number of physiologic reactions to potentially detrimental effects.     

Fibrin and fibrinolysis in infection and host defense

Summary.  Bacterial pathogens have frequently evolved and maintained the capacity to engage and/or activate hemostatic system components of their vertebrate hosts. Recent studies of mice with selected alterations in host plasminogen and other hemostatic factors have begun to reveal a seminal role of bacterial plasminogen activators and fibrin clearance in microbial pathogenesis. Bacterial pathogens appear to exploit host plasmin-mediated proteolysis to both support microbial dissemination and evade innate immune surveillance systems. The contribution of bacterial plasminogen activation to the evasion of the inflammatory response is particularly conspicuous with the plague agent, Yersinia pestis . Infection of control mice with wild-type Y. pestis leads to the formation of widespread foci containing massive numbers of free bacteria with little inflammatory cell infiltrate, whereas the loss of either the bacterial plasminogen activator, Pla, or the elimination of host plasminogen results in the accumulation of robust inflammatory cell infiltrates at sites of infection and greatly improved survival. Interestingly, fibrin(ogen) deficiency undermines the local inflammatory response observed with Pla-deficient Y. pestis and effectively eliminates the survival benefits posed by the elimination of either host plasminogen or bacterial Pla. These studies, and complementary studies with other human pathogens, illustrate that plasminogen and fibrinogen are extremely effective modifiers of the inflammatory response in vivo and critical determinants of bacterial virulence and host defense. Detailed studies of the inflammatory response in mice with genetically-imposed modifications in coagulation and fibrinolytic factors underscore the regulatory crosstalk between the hemostatic and immune systems.     

Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis

Francisella tularensis is a highly infectious gram-negative coccobacillus that causes the zoonosis tularemia. This bacterial pathogen causes a plague-like disease in humans after exposure to as few as 10 cells. Many of the mechanisms by which the innate immune system fights Francisella are unknown. Here we show that wild-type Francisella, which reach the cytosol, but not Francisella mutants that remain localized to the vacuole, induced a host defense response in macrophages, which is dependent on caspase-1 and the death-fold containing adaptor protein ASC. Caspase-1 and ASC signaling resulted in host cell death and the release of the proinflammatory cytokines interleukin (IL)-1beta and IL-18. F. tularensis-infected caspase-1- and ASC-deficient mice showed markedly increased bacterial burdens and mortality as compared with wild-type mice, demonstrating a key role for caspase-1 and ASC in innate defense against infection by this pathogen.     

Fibrin-mediated protection against infection-stimulated immunopathology

Fibrin, a product of the blood coagulation cascade, accompanies many type 1 immune responses, including delayed-type hypersensitivity, autoimmunity, and graft rejection. In those settings, fibrin is thought to exacerbate inflammation and disease. Here, we evaluate roles for coagulation during infection with Toxoplasma gondii, a pathogen whose control requires robust type 1 immunity. We establish that fibrin prevents infection-stimulated blood loss, thereby performing a protective function that is essential for survival. Remarkably, fibrin does not simply protect against vascular damage caused directly by the infectious agent, but rather, protects against hemorrhage evoked by interferon-gamma, a critical mediator of type 1 immunity. This finding, to our knowledge, is the first to document a beneficial role for coagulation during type 1 immunity, and suggests that fibrin deposition protects host tissue from collateral damage caused by the immune system as it combats infection.     

Platelets in inflammation and immunity

The paradigm of platelets as mere mediators of hemostasis has long since been replaced by a dual role: hemostasis and inflammation. Now recognized as key players in innate and adaptive immune responses, platelets have the capacity to interact with almost all known immune cells. These platelet–immune cell interactions represent a hallmark of immunity, as they can potently enhance immune cell functions and, in some cases, even constitute a prerequisite for host defense mechanisms such as NETosis. In addition, recent studies have revealed a new role for platelets in immunity: They are ubiquitous sentinels and rapid first‐line immune responders, as platelet–pathogen interactions within the vasculature appear to precede all other host defense mechanisms. Here, we discuss recent advances in our understanding of platelets as inflammatory cells, and provide an exemplary review of their role in acute inflammation.     

Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential

The discovery of mammalian TLRs (Toll-like receptors), first identified in 1997 based on their homology with Drosophila Toll, greatly altered our understanding of how the innate immune system recognizes and responds to diverse microbial pathogens. TLRs are evolutionarily conserved type?I transmembrane proteins expressed in both immune and non-immune cells, and are typified by N-terminal leucine-rich repeats and a highly conserved C-terminal domain termed the TIR [Toll/interleukin (IL)-1 receptor] domain. Upon stimulation with their cognate ligands, TLR signalling elicits the production of cytokines, enzymes and other inflammatory mediators that can have an impact on several aspects of CNS (central nervous system) homoeostasis and pathology. For example, TLR signalling plays a crucial role in initiating host defence responses during CNS microbial infection. Furthermore, TLRs are targets for many adjuvants which help shape pathogen-specific adaptive immune responses in addition to triggering innate immunity. Our knowledge of TLR expression and function in the CNS has greatly expanded over the last decade, with new data revealing that TLRs also have an impact on non-infectious CNS diseases/injury. In particular, TLRs recognize a number of endogenous molecules liberated from damaged tissues and, as such, influence inflammatory responses during tissue injury and autoimmunity. In addition, recent studies have implicated TLR involvement during neurogenesis, and learning and memory in the absence of any underlying infectious aetiology. Owing to their presence and immune-regulatory role within the brain, TLRs represent an attractive therapeutic target for numerous CNS disorders and infectious diseases. However, it is clear that TLRs can exert either beneficial or detrimental effects in the CNS, which probably depend on the context of tissue homoeostasis or pathology. Therefore any potential therapeutic manipulation of TLRs will require an understanding of the signals governing specific CNS disorders to achieve tailored therapy.     

Patterns of Oligonucleotide Sequences in Viral and Host Cell RNA Identify Mediators of the Host Innate Immune System

The innate immune response provides a first line of defense against pathogens by targeting generic differential features that are present in foreign organisms but not in the host. These innate responses generate selection forces acting both in pathogens and hosts that further determine their co-evolution. Here we analyze the nucleic acid sequence fingerprints of these selection forces acting in parallel on both host innate immune genes and ssRNA viral genomes. We do this by identifying dinucleotide biases in the coding regions of innate immune response genes in plasmacytoid dendritic cells, and then use this signal to identify other significant host innate immune genes. The persistence of these biases in the orthologous groups of genes in humans and chickens is also examined. We then compare the significant motifs in highly expressed genes of the innate immune system to those in ssRNA viruses and study the evolution of these motifs in the H1N1 influenza genome. We argue that the significant under-represented motif pattern of CpG in an AU context - which is found in both the ssRNA viruses and innate genes, and has decreased throughout the history of H1N1 influenza replication in humans - is immunostimulatory and has been selected against during the co-evolution of viruses and host innate immune genes. This shows how differences in host immune biology can drive the evolution of viruses that jump into species with different immune priorities than the original host.     

Sepsis syndromes: understanding the role of innate and acquired immunity

An intact innate and acquired immune response are essential for defeating systemic microbial infections. Recognition molecules, inflammatory cells, and the cytokines they produce are the principal means for host tissues to recognize invading microbes and to initiate intercellular communication between the innate and acquired immune systems. However, activation of host innate immunity may also occur in the absence of microbial recognition, through expression of internal "danger" signals produced by tissue ischemia and necrosis. When activation of the innate immune system is severe enough, the host response itself can propel the patient into a systemic inflammatory response syndrome (SIRS), or even multiple system organ failure (MSOF) and shock. Although most patients survive the initial SIRS insult, these patients remain at increased risk of developing secondary or opportunistic infections because of the frequent onset of a compensatory anti-inflammatory response syndrome (CARS). The initial activation of the innate immune response often leads to macrophage deactivation, T-cell anergy, and the rapid apoptotic loss of lymphoid tissues, which all contribute to the development of this CARS syndrome and its associated morbidity and mortality. Initial efforts to treat the septic patient with anticytokine therapies directed at the SIRS response have been disappointing, and therapeutic efforts to modify the immune response during sepsis syndromes will require a more thorough understanding of the innate and acquired immune responses and the increased apoptosis in the lymphoid tissue.     

The innate immune response to secondary peritonitis

Secondary peritonitis continues to cause high morbidity and mortality despite improvements in medical and surgical therapy. This review combines data from published literature, focusing on molecular patterns of inflammation in pathophysiology and prognosis during peritonitis. Orchestration of the innate immune response is essential. To clear the microbial infection, activation and attraction of leukocytes are essential and beneficial, just like the expression of inflammatory cytokines. Exaggeration of these inflammatory systems leads to tissue damage and organ failure. Nonsurvivors have increased proinflammation, complement activation, coagulation, and chemotaxis. In these patients, anti-inflammatory systems are decreased in blood and lungs, whereas the abdominal compartment shows decreased neutrophil activation and decreased or stationary chemokine and cytokine levels. A later down-regulation of proinflammatory mediators with concomitant overexpression of anti-inflammatory mediators leads to immunoparalysis and failure to clear residual bacterial load, resulting in the occurrence of superimposed infections. Thus, in patients with adverse outcome, the inflammatory reaction is no longer contained within the abdomen, and the inflammatory response has shifted to other compartments. For the understanding of the host response to secondary peritonitis, it is essential to realize that the defense systems presumably are expressed differently and, in part, autonomously in different compartments.     

Innate Immunity and Neuroinflammation in the CNS: The Role of Microglia in Toll-Like Receptor-Mediated Neuronal Injury

小胶质细胞是中枢神经系统内的内源性免疫细胞,在中枢神经系统的固有免疫反应中扮演关键的角色,其主要作用是早期控制感染及激活适应性免疫系统细胞,以清除病原体。小胶质细胞引发的固有和适应性免疫反应包括前炎性因子的释放。虽然有效的免疫反应对于防御病原体的侵害是必须的,但中枢神经系统的炎症反应也会造成相应的组织损伤和神经退行性变化。Toll样受体是模式识别受体家族中一个主要成员,不仅介导固有免疫反应,也参与适应性免疫反应。通过Toll样受体,小胶质细胞能识别中枢神经系统内的病原体配体及宿主配体。虽然越来越多的证据表明Toll样受体信号通路调节中枢神经系统有益的保护反应,但其诱导的小胶质细胞活化及前炎症因子释放也介导多种中枢神经系统疾病病理过程中的神经毒性作用。因此,Toll样受体介导的小胶质细胞活化对中枢神经系统的最终作用,取决于二者之间微妙的平衡。本文主要评述中枢神经系统内Toll样受体信号通路调控的神经退行性作用。     

免疫功能紊乱在脓毒症发病中的作用及意义

有关炎症问题的研究在脓毒症领域开展得很早,目前对它的了解无论是在基础理论还是在临床实践方面也都比较深入。传统观念认为,脓毒症是一种失控的持久性炎症反应,是由感染因素诱发的全身炎症反应综合征(SIRS)。基于这种认识,人们应用大量抗炎措施治疗脓毒症,虽然在动物实验中取得了一定的疗效,但在临床应用中     

All is not Toll: new pathways in DNA recognition

Immunological defense depends on the ability of the innate immune system to recognize invading microbes as foreign and thus eliminate them. The Toll-like receptors (TLRs) help detect foreign invaders by sensing various pathogen-associated molecules, including microbial RNA and DNA. At present, it is unclear whether and how the immune system distinguishes between microbial and self nucleic acids, as host-derived RNA and DNA also stimulate TLRs. In addition, recent studies have revealed the existence of TLR-independent pathways that are activated in response to microbial and host nucleic acids.     

Immunomodulation et sepsis – Impact de l’agent pathogène

Infection begins when micro-organisms overcome host barriers and multiply within host tissue. To contain infection, the host stages an inflammatory reaction to mobilize defence systems and kill the invading micro-organisms. In most cases, the activated defence mechanisms lead to eradication of infection throught a localized inflammatory reaction. However, when the infectious stimulus cannot be contained within tissues, infectious agents, their toxins, and host-derived mediators are released into the circulation leading to a systemic inflammatory response syndrome and remote organ dysfunction. It appears that microbial organisms have coevolved with their hosts to overcome protective host barriers and in selected cases, actually take advantage of innate host responses. Many microbial pathogens avoid host responses recognition or dampen the subsequent immune activation through sophisticated interactions with host responses, but some pathogens benefit from the stimulation if inflammatory reactions. The pathogenesis of sepsis assumes that host are capable to generate unique common responses to any pathogen but also exhibit different pathogen-specific immune responses. Determining whether the unique responses are advantageous to the pathogen or to the host is essential for understanding host-pathogen interactions. In this review, we will discuss how pathogens interfere with innate and adaptative immune responses in order to evade the immune response.