The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host.

Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation

Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury

Hypoxic regulation of neutrophil function and consequences for Staphylococcus aureus infection.

Staphylococcal infection and neutrophilic inflammation can act in concert to establish a profoundly hypoxic environment. In this review we summarise how neutrophils and Staphylococcus aureus are adapted to function under hypoxic conditions, with a particular focus on the impaired ability of hypoxic neutrophils to effect Staphylococcus aureus killing.This work was supported by a Wellcome Trust Research Training Fellowship awarded to K.M.L, Papworth Hospital Research and Development Department and the NIHR Cambridge Biomedical Research Centre

Diet during pregnancy and infancy, and risk of allergic or autoimmune disease: a systematic review and meta-analysis

Background: There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. Methods and findings: Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68–0.90; I2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20–64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53–0.90; I2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10–47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow’s milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures—including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake—influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy. Conclusions: Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host.

Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation

Asthma: From Diagnosis to Endotype to Treatment.

Aaron S et al. Re-evaluation of diagnosis in adults with physician-diagnosed asthma. JAMA (1) Reviewed by Akhilesh Jha Asthma diagnosis is based on classical symptoms together with variable airflow limitation (2). Accuracy is essential to ensure appropriate long-term medication; misdiagnosis can lead to unnecessary drug-related adverse effects and medical expenditure. Lefaudeux D et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol (6) Reviewed by Martin Knolle Recent advances in asthma phenotyping (7-9) have enabled more effective and targeted asthma treatments. However, a mechanistic understanding of these inflammatory endotypes remains limited. To this end, the ‘Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes’ (U-BIOPRED) consortium has applied ‘multi-omics’ approaches to well-characterised asthma patient cohorts (10). Nair P et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med (15) Reviewed by Katharine M Lodge Patients with treatment-refractory asthma account for a large proportion of asthma healthcare costs and suffer substantial glucocorticoid-induced co-morbidities (16, 17). Type 2 immune response-driven eosinophilia is associated with severe and uncontrolled asthma (18). Interleukin 5 (IL-5), a pro-inflammatory cytokine produced by Th2 cells, promotes eosinophil recruitment and survival, and represents an important therapeutic target (19). Monoclonal antibodies against IL-5 (mepolizumab and reslizumab) or the IL-5 receptor (benralizumab) reduce exacerbation frequency in severe eosinophilic asthma, with potential for lung function and quality of life improvement (20-22)

Asthma: From Diagnosis to Endotype to Treatment.

Aaron S et al. Re-evaluation of diagnosis in adults with physician-diagnosed asthma. JAMA (1) Reviewed by Akhilesh Jha Asthma diagnosis is based on classical symptoms together with variable airflow limitation (2). Accuracy is essential to ensure appropriate long-term medication; misdiagnosis can lead to unnecessary drug-related adverse effects and medical expenditure. Lefaudeux D et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol (6) Reviewed by Martin Knolle Recent advances in asthma phenotyping (7-9) have enabled more effective and targeted asthma treatments. However, a mechanistic understanding of these inflammatory endotypes remains limited. To this end, the ‘Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes’ (U-BIOPRED) consortium has applied ‘multi-omics’ approaches to well-characterised asthma patient cohorts (10). Nair P et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med (15) Reviewed by Katharine M Lodge Patients with treatment-refractory asthma account for a large proportion of asthma healthcare costs and suffer substantial glucocorticoid-induced co-morbidities (16, 17). Type 2 immune response-driven eosinophilia is associated with severe and uncontrolled asthma (18). Interleukin 5 (IL-5), a pro-inflammatory cytokine produced by Th2 cells, promotes eosinophil recruitment and survival, and represents an important therapeutic target (19). Monoclonal antibodies against IL-5 (mepolizumab and reslizumab) or the IL-5 receptor (benralizumab) reduce exacerbation frequency in severe eosinophilic asthma, with potential for lung function and quality of life improvement (20-22)

The formation and function of the neutrophil phagosome.

Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole-like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived antimicrobial agents and granule-delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate.Supported by: Avant Doctor in Training Research Scholarship 2021/000023 (A.J.T.W); Evelyn Trust Clinical Research Fellowship (M.R.); British Infection Association (M.R.); Academy of Medical 40 Sciences Starter Grant for Clinical Lecturers (A.P.S); Medical Research Council Clinician Scientist Fellowship MR/V006118/1 (A.CM); Academy of Medical Sciences Starter Grant for Clinical Lecturers SGL024\1086 (K.M.L.); and NIHR Imperial Biomedical Research Centre (K.M.L., E.R.C.

The formation and function of the neutrophil phagosome

Funder: British Infection Association; Id: http://dx.doi.org/10.13039/501100004664Funder: Evelyn Trust; Id: http://dx.doi.org/10.13039/501100004282Funder: NIHR Imperial Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100013342Summary: Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen‐eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole‐like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase‐derived antimicrobial agents and granule‐delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate