DEspRhigh neutrophils are associated with critical illness in COVID-19

SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.

Functionalized nanoparticles with monocyte membranes and rapamycin achieve synergistic chemoimmunotherapy for reperfusion-induced injury in ischemic stroke

Background Ischemic stroke is an acute and severe neurological disease, and reperfusion is an effective way to reverse brain damage after stroke. However, reperfusion causes secondary tissue damage induced by inflammatory responses, called ischemia/reperfusion (I/R) injury. Current therapeutic strategies that control inflammation to treat I/R are less than satisfactory. Results We report a kind of shield and sword nano-soldier functionalized nanoparticles (monocyte membranes-coated rapamycin nanoparticles, McM/RNPs) that can reduce inflammation and relieve I/R injury by blocking monocyte infiltration and inhibiting microglia proliferation. The fabricated McM/RNPs can actively target and bind to inflammatory endothelial cells, which inhibit the adhesion of monocytes to the endothelium, thus acting as a shield. Subsequently, McM/RNPs can penetrate the endothelium to reach the injury site, similar to a sword, and release the RAP drug to inhibit the proliferation of inflammatory cells. In a rat I/R injury model, McM/RNPs exhibited improved active homing to I/R injury areas and greatly ameliorated neuroscores and infarct volume. Importantly, in vivo animal studies revealed good safety for McM/RNPs treatment. Conclusion The results demonstrated that the developed McM/RNPs may serve as an effective and safe nanovehicles for I/R injury therapy. Graphic abstract

TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.

Increased Neutrophil-Subset Associated With Severity/Mortality In ARDS And COVID19-ARDS Expresses The Dual Endothelin-1/VEGFsignal-Peptide Receptor (DEspR): An Actionable Therapeutic Target

Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to severe COVID19. This ‘innocent bystander’ tissue injury arises in dysregulated hyperinflammatory states from neutrophil functions and neutrophil extracellular traps (NETs) intended to kill pathogens, but injure cells instead, causing MOF. Insufficiency of prior therapeutic approaches suggest need to identify dysregulated neutrophil-subset(s) and induce subset-specific apoptosis critical for neutrophil function-shutdown and clearance. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/signal peptide receptor, DEspR, are apoptosis-resistant just like DEspR+ cancer cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID19-ARDS. Here, we report correlation of circulating DEspR+CD11b+ activated neutrophils (DESpR+actNs) and NETosing-neutrophils with severity in ARDS and in COVID19-ARDS, increased DEspR+ neutrophils and monocytes in post-mortem ARDS-patient lung sections, and neutrophil DEspR/ET1 receptor/ligand autocrine loops in severe COVID19. Unlike DEspR[-] neutrophils, ARDS patient DEspR+actNs exhibit apoptosis-resistance, which decreased upon ex vivo treatment with humanized anti-DEspR-IgG4S228P antibody, hu6g8. Ex vivo live-cell imaging of non-human primate DEspR+actNs showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data differentiate DEspR+actNs as a targetable neutrophil-subset associated with ARDS and COVID19-ARDS severity, and suggest DEspR-inhibition as a potential therapeutic paradigm. 1-sentence summary: Circulating DEspR+CD11b+ neutrophils and NETosing neutrophils are associated with severity and mortality in ARDS and COVID19-ARDS.

Post Orgasmic Illness Syndrome (POIS) and Delayed Onset Muscle Soreness (DOMS): Do They Have Anything in Common?

Post orgasmic illness syndrome is a rare, mysterious condition with an unknown pathomechanism and uncertain treatment. The symptoms of post orgasmic illness syndrome last about 2–7 days after an ejaculation. The current hypothesis proposes that the primary injury in post orgasmic illness syndrome is an acute compression proprioceptive axonopathy in the muscle spindle, as is suspected in delayed onset muscle soreness. The terminal arbor degeneration-like lesion of delayed onset muscle soreness is theorized to be an acute stress response energy-depleted dysfunctional mitochondria-induced impairment of Piezo2 channels and glutamate vesicular release. The recurring symptoms of post orgasmic illness syndrome after each ejaculation are suggested to be analogous to the repeated bout effect of delayed onset muscle soreness. However, there are differences in the pathomechanism, mostly attributed to the extent of secondary tissue damage and to the extent of spermidine depletion. The spermidine depletion-induced differences are as follows: modulation of the acute stress response, flu-like symptoms, opioid-like withdrawal and enhanced deregulation of the autonomic nervous system. The longitudinal dimension of delayed onset muscle soreness, in the form of post orgasmic illness syndrome and the repeated bout effect, have cognitive and memory consequences, since the primary injury is learning and memory-related.

Biophysical interactions between components of the tumor microenvironment promote metastasis

During metastasis, tumor cells need to adapt to their dynamic microenvironment and modify their mechanical properties in response to both chemical and mechanical stimulation. Physical interactions occur between cancer cells and the surrounding matrix including cell movements and cell shape alterations through the process of mechanotransduction. The latter describes the translation of external mechanical cues into intracellular biochemical signaling. Reorganization of both the cytoskeleton and the extracellular matrix (ECM) plays a critical role in these spreading steps. Migrating tumor cells show increased motility in order to cross the tumor microenvironment, migrate through ECM and reach the bloodstream to the metastatic site. There are specific factors affecting these processes, as well as the survival of circulating tumor cells (CTC) in the blood flow until they finally invade the secondary tissue to form metastasis. This review aims to study the mechanisms of metastasis from a biomechanical perspective and investigate cell migration, with a focus on the alterations in the cytoskeleton through this journey and the effect of biologic fluids on metastasis. Understanding of the biophysical mechanisms that promote tumor metastasis may contribute successful therapeutic approaches in the fight against cancer.

Changes of the Blood Lymphocytes On Severe Trauma Patients in Early Time

Purpose: To evaluate the relationship between the change of blood lymphocyte counts in early stages of trauma patients and the secondary tissue injury after trauma. Method: A retrospective study was conduct to include trauma patients with Injury Severity Score(ISS) ≥16 between January 1 st , 2018 and December 31 st , 2019. Lymphocyte counts of each trauma patient were collected and recorded in first 3 hours, 6-12 hours, 24-48 hours, and 49-72 hours after trauma, separately. The degree of secondary on the trauma patients were evaluated according to the results of laboratory tests, the time stay in ICU and received mechanical ventilation, and 28-day outcome. Correlation analysis was performed between lymphocytes change and the score of the secondary tissue injury in severe trauma patients. Results: The lymphocyte count within first 3 hours after trauma was significantly high,the median was 4.03×10 9 /L, then dropped significantly in 6-72 hours after trauma (median: 0.85~0.99×10 9 /L), there was a significant statistical difference between the lymphocyte count within first 3 hours after trauma and that in 6-72 hours（P=0.000). The ratios of the lymphocytes counts in 6-72 hours to that within first 3 hours after trauma were very low, the median value was 0.22-0.27. The results of regression statistical analysis showed that the change of lymphocyte counts significantly associated with the severe degree of secondary injury (P=0.000). The lymphocyte ratio change can be used to predict the possibility of trauma patients secondary severe tissue injury occurred [Area Under the Curve( AUC) on the ratios of the lymphocytes counts in 6-72 hours to that within first 3 hours after trauma was 0.789, 0.840, 0.861, respectively]. The predictive thresholds of lymphocyte ratio of the trauma patients in the study were 0.31 to 0.35, the prediction sensitivity were 78% to 89% and specificity 74% to 84%. The lymphocyte counts there was significant difference between the patients with assessed as serious secondary tissue injury(87cases) and patients without(25 cases), the median value was 0.21-0.24 , 0.38-0.62, respectively , P=0.000. Conclusion: Lymphocytes counts was significantly increased in the trauma patients with ISS score ≥16 within the first 3 hours after trauma, then decreased significantly in 6-72 hours after trauma. The change of lymphocyte count was significant relationship with the degree of secondary tissue injury, that can be used to predict the degree of secondary severe tissue injury occurred by inflammatory reaction in trauma patients.

Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20th century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg2+ (ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.

Controlling Cytokine Storm Is Vital in COVID-19

Corona virus disease 2019 (COVID-19) has caused a global outbreak and severely posed threat to people’s health and social stability. Mounting evidence suggests that immunopathological changes, including diminished lymphocytes and elevated cytokines, are important drivers of disease progression and death in coronavirus infections. Cytokine storm not only limits further spread of virus in the body but also induces secondary tissue damage through the secretion of large amounts of active mediators and inflammatory factors. It has been determined that cytokine storm is a major cause of deaths in COVID-19; therefore, in order to reverse the deterioration of severe and critically ill patients from this disease, the cytokine storm has become a key therapeutic target. Although specific mechanisms of the occurrences of cytokine storms in COVID-19 have not been fully illuminated, hyper-activated innate immune responses, and dysregulation of ACE2 (angiotensin converting enzyme 2) expression and its downstream pathways might provide possibilities. Tailored immunoregulatory therapies have been applied to counteract cytokine storms, such as inhibition of cytokines, corticosteroids, blood purification therapy, and mesenchymal stem cell therapy. This review will summarize advances in the research of cytokine storms induced by COVID-19, as well as potential intervention strategies to control cytokine storms.