Alarmins MRP8 and MRP14 Induce Stress Tolerance in Phagocytes under Sterile Inflammatory Conditions

Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14(-/-) mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation

Activated Tissue-Resident Mesenchymal Stromal Cells Regulate Natural Killer Cell Immune and Tissue-Regenerative Function

The interaction of mesenchymal stromal cells (MSCs) with natural killer (NK) cells is traditionally thought of as a static inhibitory model, whereby resting MSCs inhibit NK cell effector function. Here, we use a dynamic in vitro system of poly(I:C) stimulation to model the interaction of NK cells and tissue-resident MSCs in the context of infection or tissue injury. The experiments suggest a time-dependent system of regulation and feedback, where, at early time points, activated MSCs secrete type I interferon to enhance NK cell effector function, while at later time points TGF-β and IL-6 limit NK cell effector function and terminate inflammatory responses by induction of a regulatory senescent-like NK cell phenotype. Importantly, feedback of these regulatory NK cells to MSCs promotes survival, proliferation, and pro-angiogenic properties. Our data provide additional insight into the interaction of stromal cells and innate immune cells and suggest a model of time-dependent MSC polarization and licensing

SARS-CoV-2/COVID-19: Evolving Reality, Global Response, Knowledge Gaps and Opportunities

Approximately 3 billion people around the world have gone into some form of social separation to mitigate the current SARS-CoV-2 pandemic. The uncontrolled influx of patients in need of emergency care has rapidly brought several national health systems to near-collapse with deadly consequences to those afflicted by COVID-19 and other critical diseases associated with COVID-19. Solid scientific evidence regarding SARS-CoV-2/COVID-19 remains scarce; there is an urgent need to expand our understanding of the SARS-CoV-2 pathophysiology to facilitate precise and targeted treatments. The capacity for rapid information dissemination has emerged as a double-edged sword; the existing gap of high-quality data is frequently filled by anecdotal reports, contradictory statements and misinformation. This review addresses several important aspects unique to the SARS-CoV-2/COVID-19 pandemic highlighting the most relevant knowledge gaps and existing windows-of-opportunity. Specifically, focus is given to SARS-CoV-2 immunopathogenesis in the context of experimental therapies and pre-clinical evidence and their applicability in supporting efficacious clinical trial planning. The review discusses the existing challenges of SARS-CoV-2 diagnostics and the potential application of translational technology for epidemiological predictions, patient monitoring and treatment decision-making in COVID-19. Furthermore, solutions for enhancing international strategies in translational research, cooperative networks and regulatory partnerships are contemplated. Address reprint requests to Marc Maegele, Department of Trauma and Orthopaedic Surgery, Cologne-Merheim Medical Center (CMMC), Institute for Research in Operative Medicine (IFOM), University of Witten/Herdecke, Cologne-Merheim Campus, Cologne, Germany. E-mail: [email protected]; Marcin F. Osuchowski, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Trauma Research Center, Donaueschingenstrasse 13, 1200 Vienna, Austria. E-mail: [email protected]. Received 22 April, 2020 Revised 29 April, 2020 Accepted 5 May, 2020 Osuchowski M: no conflict of interest Aletti F: no conflict of interest Cavaillon J-M: no conflict of interest Flohe SB: no conflict of interest Giamarellos-Bourboulis EJ: honoraria from AbbVie USA, Abbott CH, InflaRx GmbH, MSD Greece, XBiotech Inc. and Angelini Italy; independent educational grants from AbbVie, Abbott, Astellas Pharma Europe, AxisShield, bioMérieux Inc, InflaRx GmbH, and XBiotech Inc.; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). Huber-Lang M: no conflict of interest Relja B: no conflict of interest Skirecki T: no conflict of interest Szabó A: no conflict of interest Maegele M: no conflict of interest © 2020 by the Shock Societ

Is There an Impact of Concomitant Injuries and Timing of Fixation of Major Fractures on Fracture Healing? A Focused Review of Clinical and Experimental Evidence

OBJECTIVE: This review aims to summarize current knowledge regarding the underlying patho-mechanisms of delayed fracture healing in polytraumatized patients. DATA SOURCES AND STUDY SELECTION: The following search terms were used: "fracture", "hemorrhage," "chest trauma," "inflammation," "inflammatory response," "fracture healing," "delayed healing," "nonunion," "fracture stabilisation," "intramedullary nailing," "external fixation," "early total care," and "damage control." Medline, Embase, and Cochrane Library were searched for studies published between January 1, 1990 through March 30, 2014. Of 1322 publications, 68 were included in the current summary. CONCLUSION: Concomitant injuries and the strategy for fracture stabilization seem to affect bone metabolism and fracture healing. Among the relevant patho-mechanisms, interactions between the local and systemic inflammatory response seem to play a role. However, the consequences of fracture fixation strategies in case of severe concomitant injuries on local inflammation and bone healing remain unknown. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19