Centre for Inflammation Research

Neutrophils are short lived innate immune cells, critical for pathogen control. They are the most abundant type of leucocyte in the circulation and, in response to inflammatory stimuli, are rapidly recruited into the tissues with the circulating population being replenished from the bone marrow. Although traditionally considered simplistic antimicrobial cells with limited heterogeneity, recent studies have highlighted the diversity of neutrophil phenotypes and their potential as therapeutic targets. Neutrophils rewire their metabolism in response to nutrient availability and inflammatory cues in order to function in diverse, and often hostile, inflammatory environments. In this review we highlight how metabolism fuels neutrophil effector function in diverse tissues and how this can impact disease processes including infection, inflammation and malignancy but also presents novel therapeutic targets.

Neutrophils are abundant innate immune cells with remarkable plasticity, capable of exerting both antitumour and protumour functions. Beyond their local roles in the tumour microenvironment, recent studies highlight tumour-induced granulopoiesis as a systemic process by which cancers rewire haematopoiesis to expand immature neutrophils with immunosuppressive and tumour-promoting activity. Sustained by tumour-derived cytokines, chemokines and alarmins, tumour-induced granulopoiesis activates developmental programmes such as STAT3-C/EBPβ and RORC1, driving persistent neutrophilia and systemic immune suppression. Here, we review neutrophil maturation and heterogeneity, their dual roles in tumour initiation and progression, and the emerging recognition of tumour-induced granulopoiesis as a critical axis of tumour-host interaction with clinical and therapeutic implications.

Traumatic brachial plexus injuries (TBPI) are life-changing and can lead to permanent changes in function and pain within the arm and hand. Historically, TBPI research has reflected the priorities of researchers and clinicians rather than those with personal experience of living with a TBPI. The James Lind Alliance (JLA), supported by the National Institute for Health Research, has developed a rigorous methodology for increasing public engagement in research by giving an equal voice to patients, carers, and healthcare providers to ensure that their concerns are represented in future health research programmes. These projects are called priority setting partnerships (PSPs). A JLA PSP, comprising patients, carers and clinicians, was created and completed to agree future research priorities in adult TBPI. The JLA PSP methodology was followed throughout. One-hundred and fifty-four respondents replied to an initial survey generating 704 questions. These were assessed, grouped and combined to create 68 summary questions or 'uncertainties'. Three were excluded after literature review suggested they had already been answered by research. Seventy-nine respondents answered an interim prioritization survey, choosing their top ten from the summary questions. In a workshop, nine patients, two carers and 11 clinicians met, discussed and ranked the top 22 questions from the interim survey to identify the top 10 research priorities. Psychology, physical therapy treatments and management pathways were among the top ranked priorities. These results will inform researchers and funding bodies about research priorities for patients, carers and clinicians to direct future research on TBPI. V.

This study evaluates the dynamic changes in the quantity and quality of neutrophil-derived cell-free DNA (cfDNA) in whole blood and plasma samples from severe thermal and traumatically injured patients. Neutrophil-derived cfDNA, a component of neutrophil extracellular traps (NETs), is released during immune responses to injury and infection. Excessive NET formation mediates inflammation, tissue damage, and coagulopathy. Increased cfDNA levels in burn and trauma patients are reported to be associated with poor clinical outcomes, indicating their potential as biomarkers for predicting sepsis and MODS. Blood samples were obtained from two cohorts of burns (n = 96) and trauma (n = 147) patients. Neutrophil-derived cfDNA was quantified in plasma by SYTOX Green fluorescence and the size of extracted DNA was measured by electrophoresis. A microfluidic assay was also performed to capture NET-derived chromatin from burn patients' fresh whole blood samples. Captured NETs were stained with SYTOX green and anti-citrullinated histone antibodies. Stimulated whole blood or isolated neutrophils from healthy controls were used to generate NETs as positive controls. Circulating cfDNA levels were significantly elevated in plasma from both burns (days 1-14 postinjury) and trauma patients (<1-72 hours) compared to healthy controls. Electrophoresis revealed a prominent nucleosome band (~150 base pairs) in both burns and trauma plasma, with nucleosome oligomers detected within ultra-early samples (<1-hour posttrauma). The density of nucleosome bands correlated with cfDNA concentrations. Microfluidic capture of circulating NET-derived chromatin demonstrated increased levels in whole blood from burns, particularly at day 1 postinjury. NET-derived chromatin, cfDNA, and nucleosomes are elevated following severe burns and trauma. The dynamic changes in cDNA support their contribution to inflammation and as a key biomarker.

Background Real-world evidence concerning the cardiovascular (CV) risk of umeclidinium (UMEC) monotherapy or UMEC/vilanterol (VI) is scarce. This real-world study investigated CV risk in new users of UMEC or UMEC/VI versus new users of tiotropium (TIO) in patients with chronic obstructive pulmonary disease (COPD). Methods This prospective, observational, multinational, cohort study enrolled patients ≥18 years with COPD who initiated UMEC, UMEC/VI or TIO between 2 February 2016 and 31 January 2023. Non-inferiority (95% confidence interval [CI] upper bound &lt;2.0) of UMEC and UMEC/VI to TIO was compared for the time-to-first event (hazard ratio [HR] over 24 months) of a composite CV endpoint of myocardial infarction, stroke, heart failure or sudden cardiac death. Stabilised inverse probability of treatment weighting adjusted for differences in baseline covariate balance between groups. Incidence rates for the composite CV endpoint were calculated. Results In total, 6606 patients were enrolled; 6165 were included in the analysis. Both UMEC (n=1246) and UMEC/VI (n=2448) were non-inferior to TIO (n=2471) for the risk of the composite CV endpoint (adjusted HR [95% CI]: UMEC versus TIO: 1.254 [0.830–1.896]; UMEC/VI versus TIO: 1.352 [0.952–1.922]). Unadjusted composite CV incidence rates were low across cohorts (incidence rate [95% CI] per 100 person-years: UMEC: 1.157 [0.814–1.594]; UMEC/VI: 1.287 [1.034–1.584]; TIO: 0.924 [0.716–1.174]). Conclusions Both UMEC and UMEC/VI were non-inferior to TIO for composite CV risk, suggesting that physicians may consider escalating patients to dual bronchodilator therapy if COPD symptoms are not effectively managed with monotherapy.

BackgroundTraumatic brain injury (TBI) is a major cause of death and disability worldwide. Mobilization is defined as the application of assisted movement and physical therapy to hospitalized patients, including progressive exercise and ambulation programs. While early mobilization in the intensive care unit (ICU) has been shown to be a safe and effective intervention to improve patient outcomes in the general ICU cohort, there is currently limited evidence specific to patients with acute TBI. The aim of this service evaluation was to identify current mobilization activity and functional outcomes in patients admitted to the ICU at our institution following an acute TBI.MethodsA single-center retrospective service evaluation was performed for all patients, over 16 years-old, admitted to the ICU at our institution (a Level 1 major trauma center) with an acute TBI between January 2022 and November 2024. Patient demographics, ICU admission details, TBI severity (based on the Glasgow Coma Scale [GCS]) and functional outcomes were extracted. Mobilization outcomes included the timing of the commencement of mobilization (defined as sitting on the edge of the bed or better) and mobilization status, defined using the Manchester Mobility Scale (MMS).ResultsThe service evaluation included 353 patients, of whom 56.0% had severe TBI (GCS: 3–7). Mobilization was achieved in ICU for 53.0% of patients, with a further 18.1% first mobilized on a hospital ward post-ICU discharge. The first mobilization occurred at a median of 11 days (interquartile range: 6–18) after ICU admission. In patients surviving to ICU discharge, 28.9% had an MMS of 1 (bed-based exercises) at this time, with only 9.1% achieving an MMS of 7 (mobilizing 30 meters or more). Analysis by TBI severity found a significant decline in in-hospital mobilization rates with increasing TBI severity (90.7% vs. 58.4% for mild vs. severe TBI; p < 0.001), with a corresponding increase in the time to the first mobilization (median: 6 vs. 13 days for mild vs. severe TBI; p < 0.001).ConclusionAcute TBI patients admitted to the ICU at our institution had low rates of mobilization and achieved low levels of mobility at ICU discharge. This service evaluation highlights the need for prospective studies into early mobilization practices in the neurotrauma ICU.

The microbiological diagnosis of severe pneumonia in intensive care unit (ICU) patients remains challenging. We investigated whether amplicon-based sequencing (ABS) could provide additional value in this setting. Bacterial 16S rRNA coupled with fungal internal transcribed spacer (ITS) ABS was compared with standard of care (SOC) comprising cultures, PCR and galactomannan on bronchoalveolar lavages of immunosuppressed and immunocompetent ICU patients presenting severe pneumonia (n = 24) and noninfected lung-transplanted patients (n = 12). The ABS-matched SOC results were complete for 20/36 (55.5%) samples. Regarding 16S rRNA, ten samples showed partial agreement, whereas five others were fully discordant. Discordances were observed mainly for gram-negative organisms, either for quantification (Enterobacteria) or identification (Enterobacter sp., Haemophilus sp.). Only 1 of the 36 ITS results were discordant with the SOC results. The ABS has proven to be more valuable in immunosuppressed patients. Despite limitations in bacterial identification, pathogens not reported by SOC were detected in 8 samples (coinfections, bacterial superinfections from viral pneumonia). ITS identification was reliable, and semiquantification helped distinguish P. jirovecii infection and colonization. The correlation between galactomannan and ITS was good. While 16S rRNA sequencing is interesting for severe pneumonia of undefined aetiology in IS patients, ITS could provide additional diagnostic value for severe fungal pneumonia.

Motile cells often face microenvironmental constraints and obstacles that force them to extend multiple protrusions. However, the analysis of shape dynamics during directional decision-making has been restricted to single junctions. Here, we combined live-cell imaging and a coarse-grained model to study the migratory behavior of highly branched cells while simultaneously facing several junctions. The theoretical model predicts that the choice of a new direction is determined by the competition between the cellular protrusions in the form of seesaw oscillations. We found that macrophages and endothelial cells display different regimes moving on hexagonal networks, despite sharing a mesenchymal (i.e., adhesion-dependent) migratory strategy. The model describes the motility of both cell types and reveals a trade-off between branching and speed: Having many protrusions allows local microenvironmental exploration for directional cues, but long-range migration efficiency improves with fewer protrusions. Collectively, our data highlight the relevance and provide insights for the regulation of shape dynamics during cell navigation in complex geometries.