Publications by authors named "Derek Gilroy"

Using a model of UV-killed E. coli driven dermal inflammation in healthy human volunteers, we originally reported that following inflammatory resolution there was infiltration of macrophages, which, through prostanoids including prostaglandin (PG) E, imprints long-term tissue immunity. In addition to the prostanoids, data on levels of Specialised Pro-Resolution Lipid Mediators (SPMs) throughout inflammatory onset, resolution and post-resolution phases of this model were presented, but as illustrations rather than as primary data.

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  • Dendritic cells (DC) are essential immune cells that connect the body's innate and adaptive immune responses, with two main types: plasmacytoid DC (pDC) and conventional DC (cDC).
  • Research using in vivo deuterium-glucose labeling revealed that a specific subset of cDC known as AXL+ Siglec6+ DC (ASDC) circulates in the bloodstream for about 2.16 days, while other cDC types have slightly shorter lifespans.
  • The study also showed that ASDC are quickly recruited to inflamed areas, highlighting their role in managing immune responses during inflammation and suggesting new insights into the behavior of different DC subsets.
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  • Phagocytosis is a key immune function of white blood cells (leucocytes), but current models can't measure it in human tissues directly.
  • Researchers developed a new method using intradermal injection of methylene blue-labelled E. coli (MBEC) that allows for the measurement of this process in human skin.
  • The study showed that neutrophils and monocytes from inflamed tissue took up more MB than those in blood, demonstrating the model's potential for various research applications, including understanding phagocyte biology and infection risks in specific populations.
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  • Recent research indicates that resolving inflammation is more complex than previously thought, involving a prolonged phase of immune activity rather than a simple return to balance.
  • Following initial lung inflammation caused by Streptococcus pneumoniae, specific immune cells like memory T cells and various macrophages re-enter the tissue, showing changes in their genetic activity that facilitate further immune responses.
  • Blocking prostaglandin E2 (PGE2) signaling, particularly through the EP4 receptor, leads to reduced T cell populations and increased tissue damage, highlighting the importance of PGE2 in nurturing T cell development and preventing injury during the immune response recovery phase.
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Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKCD48 macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution.

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Neonates are relatively protected from non-neonatal pathogens by unclear mechanisms. In this issue of Immunity, Bee et al. show that resistance to Streptococcus pneumoniae in neonatal mice is mediated by dampened neutrophil efferocytosis, accumulation of aged neutrophils, and enhanced CD11b-dependent bacterial opsonophagocytosis.

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Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior.

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  • The liver is constantly exposed to bacterial products from the gut but usually maintains a tolerant state; understanding how this tolerance can shift to immunity or pathology is crucial for improving liver disease treatments.
  • A specific type of T cell, called CD14CD8 T cells, is found in high numbers in the liver, particularly in liver transplants and conditions like cirrhosis, and they show unique activation and immunomodulatory capabilities.
  • These CD14CD8 T cells can be influenced by bacterial components and local tissue signals, enhancing their ability to interact with the environment and potentially improve anti-tumor and antiviral responses.
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Background: Inflammation control is a fundamental part of chronic care in patients with a history of cancer and comorbidity. As the risk-benefit profile of anti-inflammatory drugs is unclear in survivors of cancer, GPs and patients could benefit from alternative non-pharmacological treatment options for dysregulated inflammation. There is a potential for home-built environment (H-BE) interventions to modulate inflammation; however, discrepancies exist between studies.

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The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse.

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  • The Omicron variant (B.1.1.529) of SARS-CoV-2 has many mutations that make it highly transmissible and partially able to evade neutralizing antibodies, but vaccinated individuals still have some protection against severe disease due to strong cellular immunity.
  • In a study involving healthcare workers who received three doses of the BioNTech mRNA vaccine, it was found that their B and T cell responses were enhanced against older variants but less effective against the Omicron spike protein.
  • Those previously infected with earlier variants (like Alpha) had reduced antibody responses against Omicron, while uninfected individuals who got infected with Omicron showed improved immunity to earlier variants but weaker responses against Omicron itself.
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The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty-four healthy male volunteers received a two-and-a-half-day twice daily (b.

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Background & Aims: Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction.

Methods: Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function.

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ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli.

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Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.

Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms.

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Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA-mimetics (QNX-sLXms).

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Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism.

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Background: Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.

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We have previously shown that healthy older adults exhibit reduced cutaneous immune responses during a varicella zoster virus (VZV) antigen challenge that correlated with a nonspecific inflammatory response to the injection itself. Here we found that needle damage during intradermal injections in older adults led to an increase in the number of cutaneous senescent fibroblasts expressing CCL2, resulting in the local recruitment of inflammatory monocytes. These infiltrating monocytes secreted prostaglandin E2, which inhibited resident memory T cell activation and proliferation.

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While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase.

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Host immunity is required to clear SARS-CoV-2, and inability to clear the virus because of host or pathogen factors renders those infected at risk of poor outcomes. Estimates of those who are able to clear the virus with asymptomatic or paucisymptomatic COVID-19 remain unclear, and dependent on widespread testing. However, evidence is emerging that in severe cases, pathological mechanisms of hyperinflammation and coagulopathy ensue, the former supported by results from the RECOVERY trial demonstrating a reduction in mortality with dexamethasone in advanced COVID-19.

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