IL-33 regulates age-dependency of long-term immune dysfunction induced by sepsis

Sepsis survival in adults is commonly followed by immunosuppression and increased susceptibility to secondary infections. However, the long-term immune consequences of pediatric sepsis are unknown. Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages, and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. In contrast to adults, infant mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in post-septic adults but not infant mice. Impaired IL-33 production in post-septic infant mice was associated with increased DNA-methylation on lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in infant mice. Clinically, adults but not pediatric post-septic patients exhibited higher counts of Tregs and sera IL-33 levels. Hence, we describe a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression.

The impact of the COVID-19 pandemic on non-COVID induced sepsis survival

Background The COVID-19 pandemic has taken a toll on health care systems worldwide, which has led to increased mortality of different diseases like myocardial infarction. This is most likely due to three factors. First, an increased workload per nurse ratio, a factor associated with mortality. Second, patients presenting with COVID-19-like symptoms are isolated, which also decreases survival in cases of emergency. And third, patients hesitate to see a doctor or present themselves at a hospital. To assess if this is also true for sepsis patients, we asked whether non-COVID-19 sepsis patients had an increased 30-day mortality during the COVID-19 pandemic. Methods This is a post hoc analysis of the SepsisDataNet.NRW study, a multicentric, prospective study that includes septic patients fulfilling the SEPSIS-3 criteria. Within this study, we compared the 30-day mortality and disease severity of patients recruited pre-pandemic (recruited from March 2018 until February 2020) with non-COVID-19 septic patients recruited during the pandemic (recruited from March 2020 till December 2020). Results Comparing septic patients recruited before the pandemic to those recruited during the pandemic, we found an increased raw 30-day mortality in sepsis-patients recruited during the pandemic (33% vs. 52%, p = 0.004). We also found a significant difference in the severity of disease at recruitment (SOFA score pre-pandemic: 8 (5 - 11) vs. pandemic: 10 (8 - 13); p < 0.001). When adjusted for this, the 30-day mortality rates were not significantly different between the two groups (52% vs. 52% pre-pandemic and pandemic, p = 0.798). Conclusions This led us to believe that the higher mortality of non-COVID19 sepsis patients during the pandemic might be attributed to a more severe septic disease at the time of recruitment. We note that patients may experience a delayed admission, as indicated by elevated SOFA scores. This could explain the higher mortality during the pandemic and we found no evidence for a diminished quality of care for critically ill sepsis patients in German intensive care units.

A novel IL-10 – DEL-1 axis promotes granulopoiesis and sepsis survival in early life

Newborns’ susceptibility to infection is mainly attributed to decreased neutrophil bone marrow reserves and peripheral blood neutropenia. However, the regulation of neonatal neutrophil kinetics in sepsis remains poorly understood. We demonstrate herein that the developmental endothelial locus (DEL-1) is elevated in early life and is integral to a protective host response in neonates, by supporting emergency granulopoiesis. DEL-1-deficient neonate mouse pups subjected to sepsis displayed diminished bone marrow numbers of neutrophils and granulocyte-macrophage progenitors, leading to neutropenia, exaggerated bacteremia, and increased mortality; defects that were rescued by DEL-1 administration. Contrary to adult mice, DEL-1 was not downregulated upon neonatal sepsis. The sustained production of DEL-1 under newborn sepsis was attributed to a high IL-10/IL-17A ratio, as we IL-10 upregulated DEL-1. The expression of DEL-1 and its effect in emergency granulopoiesis in neonates was diminished by anti-IL-10-Receptor blockage. Consistent with the mouse findings, DEL-1 and neutrophil numbers were higher in septic human adult and neonate patients with high IL-10/IL-17A ratio. Furthermore, septic patients with high DEL-1 exhibited lower mortality rates compared to patients with low DEL-1. These findings highlight the role of a hitherto unappreciated IL-10–DEL-1 axis in supporting emergency granulopoiesis, preventing neutropenia and promoting sepsis survival in early life.

Bacteria and Sepsis: Microbiome to the Rescue?

The microbiome is the metagenome of all microbes that live on and within every individual, and evidence for its role in the pathogenesis of a variety of diseases has been increasing over the past several decades. While there are various causes of sepsis, defined as the abnormal host response to infection, the host microbiome may provide a unifying explanation for discrepancies that are seen in septic patient survival based on age, sex, and other confounding factors. As has been the case for other human diseases, evidence exists for the microbiome to control patient outcomes after sepsis. In this review, associative data for the microbiome and sepsis survival are presented with causative mechanisms that may be at play. Finally, clinical trials to manipulate the microbiome in order to improve patient outcomes after sepsis are presented as well as areas of potential future research in order to aid in the clinical treatment of these patients.

Role of Complement and Histones in Sepsis

The wide use of the mouse model of polymicrobial sepsis has provided important evidence for events occurring in infectious sepsis involving septic mice and septic humans. Nearly 100 clinical trials in humans with sepsis have been completed, yet there is no FDA-approved drug. Our studies of polymicrobial sepsis have highlighted the role of complement activation products (especially C5a anaphylatoxin and its receptors C5aR1 and C5aR2) in adverse effects of sepsis. During sepsis, the appearance of these complement products is followed by appearance of extracellular histones in plasma, which have powerful proinflammatory and prothrombotic activities that cause cell injury and multiorgan dysfunction in septic mice. Similar responses occur in septic humans. Histone appearance in plasma is related to complement activation and appearance of C5a and its interaction with its receptors. Development of the cardiomyopathy of sepsis also depends on C5a, C5a receptors and histones. Neutralization of C5a with antibody or absence of C5aR1 blocks appearance of extracellular histones and cell and organ failure in sepsis. Survival rates in septic mice are greatly improved after blockade of C5a with antibody. We also review the various strategies in sepsis that greatly reduce the development of life-threatening events of sepsis.

Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis

Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.