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.
Maternal microbiota in pregnancy and early life McDonald, Braedon; McCoy, Kathy D
Science (American Association for the Advancement of Science),
2019-Sep-06, 2019-09-06, 20190906, Letnik:
365, Številka:
6457
Journal Article
Recenzirano
The maternal microbiota shape offspring development, including susceptibility to some illnesses
A microbial bond is shared between mother and child that renders the age-old dichotomy of “nature ...versus nurture” obsolete. Molded by both host biology and the physical relationship between mother and child, this microbial connection is formed at the earliest moments of life when the newborn's skin and mucosal surfaces are seeded with microorganisms that inhabit the mother's body, referred to as the maternal microbiota. This initial microbial exposure establishes an early-life microbiota that engages in a mutualistic relationship with the host, and leaves a lasting impression on childhood development that can control the balance between health and disease. The quest to understand this microbial bond has uncovered exciting new discoveries about host–microbial mutualism and immune development in early life, while simultaneously revolutionizing our understanding of how certain traits and diseases are passed down through generations.
Despite their humble origins as anuclear fragments of megakaryocytes, platelets have emerged as versatile mediators of thrombosis and immunity. The diverse spectrum of platelet functions are on full ...display during the host response to severe infection and sepsis, with platelets taking center-stage in the intravascular immune response to blood-borne pathogens. Platelets are endowed with a comprehensive armamentarium of pathogen detection systems that enable them to function as sentinels in the bloodstream for rapid identification of microbial invasion. Through both autonomous anti-microbial effector functions and collaborations with other innate immune cells, platelets orchestrate a complex intravascular immune defense system that protects against bacterial dissemination. As with any powerful immune defense system, dysregulation of platelet-mediated intravascular immunity can lead to profound collateral damage to host cells and tissues, resulting in sepsis-associated organ dysfunction. In this article, the cellular and molecular contributions of platelets to intravascular immune defenses in sepsis will be reviewed, including the roles of platelets in surveillance of the microcirculation and elicitation of protective anti-bacterial responses. Mechanisms of platelet-mediated thromboinflammatory organ dysfunction will be explored, with linkages to clinical biomarkers of platelet homeostasis that aid in the diagnosis and prognostication of human sepsis. Lastly, we discuss novel therapeutic opportunities that take advantage of our evolving understanding of platelets and intravascular immunity in severe infection.
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.
Recruitment of leukocytes from the bloodstream to inflamed tissues requires a carefully regulated cascade of binding interactions between adhesion molecules on leukocytes and endothelial cells. ...Adhesive interactions between CD44 and hyaluronan (HA) have been implicated in the regulation of immune cell trafficking within various tissues. In this review, the biology of CD44-HA interactions in cell trafficking is summarized, with special attention to neutrophil recruitment within the liver microcirculation. We describe the molecular mechanisms that regulate adhesion between neutrophil CD44 and endothelial HA, including recent evidence implicating serum-derived hyaluronan-associated protein as an important co-factor in the binding of HA to CD44 under flow conditions. CD44-HA-mediated neutrophil recruitment has been shown to contribute to innate immune responses to invading microbes, as well as to the pathogenesis of many inflammatory diseases, including various liver pathologies. As a result, blockade of neutrophil recruitment by targeting CD44-HA interactions has proven beneficial as an anti-inflammatory treatment strategy in a number of animal models of inflammatory diseases.
Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ...ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFN
neutrophils, downregulated interferon-stimulated genes and activated IL-1R2
neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFN
neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.
Liberation of damage-associated molecular patterns (DAMPs) following tissue injury and necrotic cell death leads to the induction of sterile inflammation. A hallmark of acute inflammation is the ...recruitment of neutrophils to injured tissues. This review focuses on the journey of neutrophils to sites of sterile inflammation and the cellular and molecular mechanisms that choreograph this complex voyage. We review the pathway of leukocyte recruitment, with emphasis on recent additions to our understanding of intravascular neutrophil migration. The contributions of various tissue-resident sentinel cell populations to the detection of danger signals (DAMPs) and coordination of neutrophil recruitment and migration are discussed. In addition, we highlight recent data on the control of neutrophil chemotaxis towards sites of sterile inflammation, including new insight into the temporal and spatial regulation of chemoattractant guidance signals that direct cell migration. Given that inappropriate neutrophilic inflammation is a cornerstone in the pathogenesis of many diseases, a complete understanding of the choreography of neutrophil recruitment to sites of sterile inflammation may uncover new avenues for therapeutic interventions to treat inflammatory pathologies.
Eradication of pathogens from the bloodstream is critical to prevent disseminated infections and sepsis. Kupffer cells in the liver form an intravascular firewall that captures and clears pathogens ...from the blood. Here, we show that the catching and killing of circulating pathogens by Kupffer cells in vivo are promoted by the gut microbiota through commensal-derived D-lactate that reaches the liver via the portal vein. The integrity of this Kupffer cell-mediated intravascular firewall requires continuous crosstalk with gut commensals, as microbiota depletion with antibiotics leads to a failure of pathogen clearance and overwhelming disseminated infection. Furthermore, administration of purified D-lactate to germ-free mice, or gnotobiotic colonization with D-lactate-producing commensals, restores Kupffer cell-mediated pathogen clearance by the liver firewall. Thus, the gut microbiota programs an intravascular immune firewall that protects against the spread of bacterial infections via the bloodstream.
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•The gut microbiota promotes clearance of pathogens from the bloodstream by the liver•Commensal D-lactate programs Kupffer cells to capture and kill circulating pathogens•Dysbiosis causes impaired Kupffer cell function, leading to disseminated infection
McDonald et al., used gnotobiotic mice and in vivo imaging to show that clearance of circulating pathogens by Kupffer cells in the liver is governed by the gut microbiota and its production of D-lactate, which reaches the liver via the portal vein and programs Kupffer cells to capture and kill pathogens in the bloodstream.
Neutrophils are recruited from the blood to sites of sterile inflammation, where they contribute to wound healing but may also cause tissue damage. By using spinning disk confocal intravital ...microscopy, we examined the kinetics and molecular mechanisms of neutrophil recruitment to sites of focal hepatic necrosis in vivo. Adenosine triphosphate released from necrotic cells activated the Nlrp3 inflammasome to generate an inflammatory microenvironment that alerted circulating neutrophils to adhere within liver sinusoids. Subsequently, generation of an intravascular chemokine gradient directed neutrophil migration through healthy tissue toward foci of damage. Lastly, formyl-peptide signals released from necrotic cells guided neutrophils through nonperfused sinusoids into the injury. Thus, dynamic in vivo imaging revealed a multistep hierarchy of directional cues that guide neutrophil localization to sites of sterile inflammation.
The liver is a target of many inflammatory pathologies of both infectious and noninfectious etiology. As key effectors of the innate immune system, neutrophils are critical for defense against ...microbial infections but are often the source of profound collateral damage to host tissues during disease states. In this article based on the authors’ presentation at the 2011 Society of Toxicologic Pathology Annual Symposium, they review the molecular mechanisms of neutrophil recruitment to the liver in response to sepsis/endotoxemia, as well as sterile inflammation, and discuss variations in the molecular choreography of neutrophil trafficking in response to these different insults. Furthermore, the authors discuss the functional contributions of neutrophils within the liver microvasculature during severe sepsis, including their contributions to both host defense and organ damage. Given that inappropriate neutrophilic inflammation contributes to the pathogenesis of many liver diseases, a thorough understanding of the molecular mechanisms that regulate the recruitment of neutrophils to the liver, and their functions therein, may reveal new avenues for therapeutic interventions to treat inflammatory liver pathologies.
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