Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Non-celiac gluten sensitivity: All wheat attack is not celiac

Currently, 1% of the United States population holds a diagnosis for celiac disease (CD), however, a more recently recognized and possibly related condition, “non-celiac gluten sensitivity” (NCGS) has been suggested to affect up to 6% of the United States public. While reliable clinical tests for CD exist, diagnosing individuals affected by NCGS is still complicated by the lack of reliable biomarkers and reliance upon a broad set of intestinal and extra intestinal symptoms possibly provoked by gluten. NCGS has been proposed to exhibit an innate immune response activated by gluten and several other wheat proteins. At present, an enormous food industry has developed to supply gluten-free products (GFP) with GFP sales in 2014 approaching $1 billion, with estimations projecting sales to reach$2 billion in the year 2020. The enormous demand for GFP also reflects a popular misconception among consumers that gluten avoidance is part of a healthy lifestyle choice. Features of NCGS and other gluten related disorders (e.g., irritable bowel syndrome) call for a review of current distinctive diagnostic criteria that distinguish each, and identification of biomarkers selective or specific for NCGS. The aim of this paper is to review our current understanding of NCGS, highlighting the remaining challenges and questions which may improve its diagnosis and treatment

BRYOSTATIN-1 LIMITS NEUTROPHIL TRANSENDOTHELIAL MIGRATION FOLLOWING ISCHEMIA-REPERFUSION INJURY: IMPACT FOR THERAPY

Poster presentation to the 25th Annual Meeting of the German Transplantation Society, Essen, Germany, 5–8 October 2016.Introduction and Background: Ischemia-reperfusion injury (IRI) is an inherent component of solid organ transplantation and axiomatically linked to graft damage. In the kidney, vascular endothelial cells (EC) are highly vulnerable to IRI. These cells are the first site of graft injury, while neutrophils are the first line of host defense after reperfusion. The degree of renal EC damage predicts the severity of neutrophil transendothelial migration (TEM), with neutrophils in turn orchestrating the influx of subsequent leukocytes waves into the graft. Therefore, EC integrity and neutrophil TEM represent promising targets to attenuate IRI. One drug known to stabilize EC integrity and to limit neutrophil TEM is Bryostatin-1, an activator of the EC second messenger protein kinase C delta. Therefore, we examined the role of Bryostatin-1 on neutrophil TEM in an in vitro IRI model. Methods: We used an in vitro IRI model with human umbilical vein ECs (HUVECs) and human neutrophils (approved by the ethic committee (STUDY00000261) to study the role of Bryostatin-1 in IRI-induced neutrophil TEM. HUVECs were exposed to either normoxic (21% O2) or hypoxic (1.5% O2) conditions for 20 hours (h) with and without Bryostatin-1 (1-100 nM) followed by 2 h exposure to Calcein-AM dye labeled neutrophils. TEM to saline or the chemoattractant leukotriene B4 (LTB4) was determined by measuring fluorescence intensity and myeloperoxidase (MPO) production. Results and Conclusions: Bryostatin-1 dose-dependently inhibited human neutrophil TEM under normoxic and hypoxic conditions. Bryostatin-1 (100 nM) blocked 75% (P < 0.05) of TEM toward LTB4 in normoxic conditions; this was intensified when HUVECs were placed in hypoxic conditions (83%, P < 0.001). These data were further supported by a mirrored effect when MPO production (a marker of neutrophil activation) was measured. In summary, these promising in vitro results demonstrate that our model recapitulates IRI-induced EC damage, and most importantly that Bryostatin-1 alters neutrophil TEM in an in vitro IRI model

The restorative role of annexin A1 at the blood–brain barrier

Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS vasculature, and its potential for repairing blood–brain barrier damage in disease and aging

Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field

Characterizing the anti-inflammatory and tissue protective actions of a novel Annexin A1 peptide

This work was supported by a collaborative project between Unigene Corp. and Queen Mary University of London and by the William Harvey Research Foundation. JD is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant no: 107613/Z/15/Z). MP was supported by the Wellcome Trust (grant no: 086867/Z/08)

Up-Regulation of Annexin-A1 and Lipoxin A4 in Individuals with Ulcerative Colitis May Promote Mucosal Homeostasis

PubMed ID: 22723974This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The FPR2-induced rise in cytosolic calcium in human neutrophils relies on an emptying of intracellular calcium stores and is inhibited by a gelsolin-derived PIP2-binding peptide

<p>Abstract</p> <p>Background</p> <p>The molecular basis for neutrophil recognition of chemotactic peptides is their binding to specific G-protein-coupled cell surface receptors (GPCRs). Human neutrophils express two pattern recognition GPCRs, FPR1 and FPR2, which belong to the family of formyl peptide receptors. The high degree of homology between these two receptors suggests that they share many functional and signal transduction properties, although they exhibit some differences with respect to signaling. The aims of this study were to determine whether FPR2 triggers a unique signal that allows direct influx of extracellular calcium without the emptying of intracellular calcium stores, and whether the gelsolin-derived PIP₂-binding peptide, PBP10, selectively inhibits FPR2-mediated transient rise in intracellular Ca²⁺.</p> <p>Results</p> <p>The transient rise in intracellular Ca²⁺induced by agonists for FPR1 or FPR2 in human neutrophils occurred also in the presence of a chelator of Ca²⁺(EGTA). PBP10 inhibited not only FPR2-induced oxidase activity, but also the transient rise in intracellular Ca²⁺.</p> <p>Conclusions</p> <p>Ca²⁺signaling mediated <it>via </it>FPR2 follows the same route as FPR1, which involves initial emptying of the intracellular stores. PBP10 inhibits selectively the signals generated by FPR2, both with respect to NADPH-oxidase activity and the transient rise in intracellular Ca²⁺induced by agonist exposure.</p