Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can

IntroductionNeutrophils are indispensable for host defense. 1 In addition, these cells play a detrimental role in the pathogenesis of many acute and chronic inflammatory diseases. They can cause tissue damage through aspecific activation of their repertoire of antimicrobial mechanisms. Neutrophils also inform and shape subsequent immunity 2 and can prolong inflammation by release of cytokines 3 and chemokines. 4 There is an emerging concept that neutrophils directly influence adaptive immune responses through pathogen shuttling to draining lymph nodes, 5,6 antigen presentation, 7 and modulation of T helper 1/T helper 2 responses. 8 Along this line, neutrophils have been reported to be an important component of myeloid-derived suppressor cells mediating lymphocyte suppression in various experimental models of acute 9 and chronic inflammation. 10 Targeting neutrophils in disease has mainly been focused on limiting their damaging capacity or directing their cytotoxic machinery to tumors. 11 Their immune modulatory functions have received little attention as potential targets in inflammatory diseases. This may at least in part be due to the current paradigm that these functions are of limited importance because of the generally accepted short circulatory half-life of neutrophils. Neutrophil lifespans have mainly been assessed by determination of ex vivo lifespans in culture (Ͻ 24 hours) and by transfer studies of ex vivo-manipulated neutrophils. The latter studies showed an estimated circulating half-life of approximately 8 hours in humans. 12 Ex vivo manipulation has been shown to have dramatic effects on neutrophil redistribution in vivo. 13 In mice, half-lives of 8 to 10 hours were reported when neutrophils were labeled in vivo. 14 In contrast, ex vivo labeling in mice showed that after transfer 90% of labeled neutrophils were cleared from the circulation within 4 hours, resulting in a half-life of less than 1.5 hours. 15 These differences between in vivo and ex vivo labeling strengthen our hypothesis that neutrophil transfer experiments may lead to an underestimation of neutrophil lifespan. The activation during ex vivo manipulation has probably led to retention in the lungs, 16 liver, spleen, and bone marrow (BM), 15 which may drastically reduce their circulatory half-life. To circumvent the complications introduced by ex vivo manipulation, we labeled the neutrophil pool in vivo in healthy mice and humans by administration of 2 H 2 O in drinking water. Acquisition of label and appearance of labeled neutrophils in the circulation is characterized by (1) the rate of division in the mitotic pool (MP) in the BM, (2) the transit time of newly formed neutrophils through the postmitotic pool (PMP) in the BM, and (3) the delay in mobilization of neutrophils from the PMP to the blood. With the use of a combination of gas chromatography and mass spectrometry the fraction of 2 H-labeled adenosine in the DNA of the proliferating neutrophil pool was measured, and the kinetics of the neutrophil pool was determined. Study des...

Neutrophils are essential effector cells in the host defense against invading pathogens. Recently, novel neutrophil functions have emerged in addition to their classical anti-microbial role. One of these functions is the suppression of T cell responses. In this respect, neutrophils share similarities with granulocytic myeloid-derived suppressor cells (G-MDSCs). In this review, we will discuss the similarities and differences between neutrophils and G-MDSCs. Various types of G-MDSCs have been described, ranging from immature to mature cells shaping the immune response by different immune suppressive mechanisms. However, all types of G-MDSCs share distinct features of neutrophils, such as surface markers and morphology. We propose that G-MDSCs are heterogeneous and represent novel phenotypes of neutrophils, capable of suppressing the immune response. In this review, we will attempt to clarify the differences and similarities between neutrophils and G-MDSCs and attempt to facilitate further research.

Background Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak.Methods PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342). FindingsBetween March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6•3 mL/kg predicted bodyweight (IQR 5•7-7•1), PEEP was 14•0 cm H 2 O (IQR 11•0-15•0), and driving pressure was 14•0 cm H 2 O (11•2-16•0). Median respiratory system compliance was 31•9 mL/cm H 2 O (26•0-39•9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0-15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. Interpretation In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19. Funding Amsterdam University Medical Centers, location Academic Medical Center.

Neutrophils are classically considered as cells pivotal for the first line of defense against invading pathogens. In recent years, evidence has accumulated that they are also important in the orchestration of adaptive immunity. Neutrophils rapidly migrate in high numbers to sites of inflammation (e.g., infection, tissue damage, and cancer) and are subsequently able to migrate to draining lymph nodes (LNs). Both at the site of inflammation as well as in the LNs, neutrophils can engage with lymphocytes and antigen-presenting cells. This crosstalk occurs either directly via cell–cell contact or via mediators, such as proteases, cytokines, and radical oxygen species. In this review, we will discuss the current knowledge regarding locations and mechanisms of interaction between neutrophils and lymphocytes in the context of homeostasis and various pathological conditions. In addition, we will highlight the complexity of the microenvironment that is involved in the generation of suppressive or stimulatory neutrophil phenotypes.