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.

Summary Although the function of platelets in the maintenance of hemostasis has been studied in great detail, more recent evidence has highlighted a central role for platelets in the host inflammatory and immune responses. Platelets by virtue of their large numbers and their ability to rapidly release a broad spectrum of immunomodulatory cytokines, chemokines, and other mediators act as circulating sentinels. Upon detection of a pathogen, platelets quickly activate and begin to drive the ensuing inflammatory response. Platelets have the ability to directly modulate the activity of neutrophils (phagocytosis, oxidative burst), endothelium (adhesion molecule and chemokine expression), and lymphocytes. Due to their diverse array of adhesion molecules and preformed chemokines, platelets are able to adhere to leukocytes and facilitate their recruitment to sites of tissue damage or infection. Furthermore, platelets directly participate in the capture and sequestration of pathogens within the vasculature. Platelet–neutrophil interactions are known to induce the release of neutrophil extracellular traps (NETs) in response to either bacterial or viral infection, and platelets have been shown to internalize pathogens, sequestering them in engulfment vacuoles. Finally, emerging data indicate that platelets also participate in the host immune response by directly killing infected cells. This review will highlight the central role platelets play in the initiation and modulation of the host inflammatory and immune responses.

IntroductionThe importance of community engagement has been established globally in health and wellness research. A certain degree of ambiguity remains, however, regarding the meaning of community engagement, which term has been used for various purposes and implemented in various forms. In this study, we aimed to explore the different definitions of community engagement, discuss the various objectives that have been proposed and uncover the diverse ways this concept has been implemented among researchers working for the betterment of the health and wellness of immigrant communities in host countries.Methods and analysisTaxonomy is a process for classifying complex and multifaceted matters using logical conceptual domains and dimensions for clearer way of contextualising. We will develop a taxonomy to organise the available literature on community engagement in immigrant health and wellness research in a way that captures user knowledge and understanding of its various meanings and processes. Specific methodological and analytical frameworks for systematic review and taxonomy development will guide each step. We will conduct a comprehensive systematic search in relevant databases, from inception to December 2019, using appropriate keywords followed by snowball search (single-citation tracking, reference lists). Papers will be included if they fall within predefined inclusion criteria (seen as most likely informative on elements pertaining to community engagement) and are written in English, regardless of design (conceptual, qualitative and quantitative). Two reviewers will independently employ two-stage screening (title–abstract screening followed by screening of the full text to determine inclusion). Finally, information that helps to develop taxonomy of the concept and practice of community engagement will be abstracted and used towards taxonomy development, where different levels of stakeholder research team members will be involved.Ethics and disseminationEthical approval is not required for this systematic review. We have opted for an integrated knowledge translation or a community-engaged knowledge mobilisation approach where we are engaged with community-based citizen researchers from the inception of our programme. We plan to disseminate the results of our review through meetings with key stakeholders, followed by journal publications and presentations at applicable platforms.

Sepsis is a systemic inflammatory response to infection which has a high mortality rate in the intensive care unit (ICU) resulting in 215000 deaths a year in United States. Neutrophils and platelets play an important role in the induction of inflammation and defense against infection in this pathology. Recent studies by our group have revealed that in severe sepsis TLR4 stimulated platelets interact with already adherent neutrophils. This interaction leads to the formation of Neutrophil Extracellular Traps (NETs) in the circulation, which helps to enhance bacterial trapping and clearance from the body; however, this may also enhance host injury in the liver sinusoids and pulmonary capillaries. To further elucidate the mechanisms by which activated platelets can adhere to immobilized neutrophils in the setting of sepsis, we used an in vitro flow chamber system using LPS and septic plasma as platelet stimulants. Antibodies to several adhesion molecules on platelets and neutrophils were tested. TLR4 activated platelets did not express P-Selectin on their surface and their interaction with immobilized neutrophils was not P-selectin-dependent. Findings show that LFA-1 and CD11c/CD18 on neutrophils, and JAM-A and ICAM-2 on platelets are involved in LPS-induced platelet adhesion to immobilized neutrophils. In addition, results from septic plasma stimulated platelets show that LFA-1 and CD11c/CD18, but not JAM-A, are involved in platelet adhesion to immobilized neutrophils. Blocking the adhesion molecules that take place in platelet adhesion to immobilized neutrophil could prevent NET formation and tissue damage specifically in lungs and liver capillaries providing a target for new therapeutics in this pathology.

No abstract