757 publications from this institution
The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional ‘waterfall’ model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.
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No abstract is provided for this article.
The use of bone marrow-derived stem cells from matched donors to reconstitute the immune system in patients with certain types of leukemia is now standard practice, and there is great interest in using stem cells to treat other human diseases. This approach received a major boost with the demonstration by Donald Orlic (New York Medical College, NY, USA) and colleagues that bone marrow stem cells delivered locally into an infarcted heart resulted in myocardial regeneration and a recovery in cardiac function in a mouse model of coronary heart disease. Stem cells from the bone marrow appeared to differentiate into cardiomyocytes, smooth muscle cells and endothelial cells, demonstrating the multipotent nature of the bone marrow cells used. Importantly, the infarct size was reduced, limiting the amount of scar tissue remaining. This study raises the possibility that heart-attack victims could be treated with stem cells from their own bone marrow, thus eliminating concerns about stem-cell rejection. Nature (2001) 410, 701–705. LON
No abstract is provided for this article.
No abstract is provided for this article.
Background The overuse and misuse of antibiotics significantly contributes to antimicrobial resistance (AMR). Adverse reactions to antibiotics are well documented, but their impact on patients’ behaviours requires further exploration. Aim To explore how side effects and allergies influence patients’ behaviours to prescribed antibiotic use. Design & setting A mixed-methods explanatory sequential study in England. Method A survey of 1059 adults with prior experience of antibiotic side effects was conducted. Descriptive statistics identified common side effects and behavioural responses, while chi-squared tests explored demographic differences. Focus groups were held with 21 participants, recruited through a research panel. Thematic analysis captured deeper insight into participants’ personal experiences. Results Many antibiotic side effects were identified, presenting shortly after consumption and affecting several aspects of patients’ lives. One-third of respondents (31%, n =325; 95% CI: 28-34%) were unaware of potential side effects beforehand, citing inaccessible patient information leaflets and limited communication from healthcare professionals as barriers. Almost half (42%, n =440; 95% CI: 37-47%) did not complete their antibiotic course following the side effects, with 32% ( n =142; 95% CI: 28-37%) stopping without medical advice. Many allergy diagnoses were made in childhood without follow-up assessments. Conclusion Antibiotic side effects can significantly disrupt patients’ lives and discourage appropriate use of antibiotics. Providing accessible information before prescribing may help manage expectations and support self-management of side effects. Patients with longstanding allergy labels should be encouraged to undergo reassessment to ensure that they are not contributing to AMR by unnecessarily avoiding the use of first-line antibiotics.
No abstract is provided for this article.
No abstract is provided for this article.
Abstract Lipids play crucial roles in immunity and inflammation via controlling immune cell metabolism and function. In particular, phospholipids (PLs), as essential structural elements of biological membranes, critically orchestrate innate and inflammatory responses through coordinating membrane plasticity and cellular signaling. Researches over the past decade have revealed the versatile roles of PL metabolism in innate immunity and inflammation as well as their differential physiological and pathological consequences, highlighting PL metabolites or enzymes as promising potential biomarkers and therapeutic targets. Further unveiling the spatiotemporal characteristics and mechanistic links between phospholipid metabolism, innate immunity, and the development of inflammatory diseases will add new insights into immunometabolism underlying health and diseases, and may suggest new strategies for manipulating PL metabolism toward novel immunotherapy against harmful inflammation and cancer. In this review, we discussed the roles of distinct lipids in innate immunity and inflammation, with particular focus on how phospholipid metabolism and membrane homeostasis are actively reprogrammed during the innate immune response, and how the crosstalk between phospholipids and innate immunity finally orchestrates the outcome of host defense and tissue homeostasis. We also discussed how dysregulation of PL metabolism contributes to pathological processes in inflammatory diseases, such as autoimmune diseases, cardiovascular diseases and cancers, and the potential strategies of restoring PL homeostasis for disease treatment.
Significance: Reactive oxygen species (ROS) are often considered to be undesirable toxic molecules that are generated under conditions of cellular stress, which can cause damage to critical macromolecules such as DNA. However, ROS can also contribute to the pathogenesis of cancer and many other chronic inflammatory disease conditions, including atherosclerosis, metabolic disease, chronic obstructive pulmonary disease, neurodegenerative disease, and autoimmune disease. Recent Advances: The field of ROS biology is expanding, with an emerging paradigm that these reactive species are not generated haphazardly, but instead produced in localized regions or in specific subcellular compartments, and this has important consequences for immune system function. Currently, there is evidence for ROS generation in extracellular spaces, in endosomal compartments, and within mitochondria. Intriguingly, the specific location of ROS production appears to be influenced by the type of invading pathogen (i.e., bacteria, virus, or fungus), the size of the invading pathogen, as well as the expression/subcellular action of pattern recognition receptors and their downstream signaling networks, which sense the presence of these invading pathogens. Critical Issues: ROS are deliberately generated by the immune system, using specific NADPH oxidases that are critically important for pathogen clearance. Professional phagocytic cells can sense a foreign bacterium, initiate phagocytosis, and then within the confines of the phagosome, deliver bursts of ROS to these pathogens. The importance of confining ROS to this specific location is the impetus for this perspective. Future Directions: There are specific knowledge gaps on the fate of the ROS generated by NADPH oxidases/mitochondria, how these ROS are confined to specific locations, as well as the identity of ROS-sensitive targets and how they regulate cellular signaling.
