Mycobacteria Attenuate Nociceptive Responses by Formyl Peptide Receptor Triggered Opioid Peptide Release from Neutrophils

In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR agonists to boost endogenous analgesia

Wnt5a stimulates chemotactic migration and chemokine production in human neutrophils

Wnt5a is a ligand that activates the noncanonical Wnt signaling pathways (??-catenin-independent pathways). Human neutrophils expressed several Wnt5a receptors, such as Frizzled 2, 5 and 8. Stimulation of human neutrophils with Wnt5a caused chemotactic migration and the production of two important chemokines, CXCL8 and CCL2. CCL2 production by Wnt5a was mediated by a pertussis toxin-sensitive G-protein-dependent pathway. Wnt5a also stimulated the phosphorylation of three mitogen-activated protein kinases (MAPKs: ERK, p38 MAPK and JNK) and Akt. Inhibition of ERK, p38 MAPK or JNK by specific inhibitors induced a dramatic reduction in Wnt5a-induced CCL2 production. Supernatant collected from lipopolysaccharide-stimulated macrophages induced neutrophil chemotaxis, which was significantly inhibited by anti-Wnt5a antibody. Our results suggested that Wnt5a may contribute to neutrophil recruitment, mediating the inflammation response.open4

Neuronal Chemokines: Versatile Messengers In Central Nervous System Cell Interaction

Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemokines are generally found under both physiological and pathological conditions. Whereas many reports describe chemokine expression in astrocytes and microglia and their role in the migration of leukocytes into the CNS, only few studies describe chemokine expression in neurons. Nevertheless, the expression of neuronal chemokines and the corresponding chemokine receptors in CNS cells under physiological and pathological conditions indicates that neuronal chemokines contribute to CNS cell interaction. In this study, we review recent studies describing neuronal chemokine expression and discuss potential roles of neuronal chemokines in neuron–astrocyte, neuron–microglia, and neuron–neuron interaction

Die beeinträchtigte psychische Gesundheit von medizinischem Personal in einer deutschen anästhesiologischen Klinik ist unabhängig von unmittelbarer SARS-CoV-2-Exposition - eine Längsschnitt-Beobachtungsstudie

Background: The study aimed to assess the mental well-being of healthcare professionals at a German department of anesthesiology and critical care with a specialized ICU for treatment of COVID-19 patients during the first two peaks of the 2020 pandemic, and identifying risk and protective factors.Methods: A single-center longitudinal, online-based survey was conducted in healthcare workers from a department of anesthesiology and critical care in Bavaria, the most affected federal state in Germany at the time of assessment. Validated scores for depression, anxiety, somatic disorders, burnout, resilience, and self-management were used and complemented by questions about perceived COVID-19-related stressors. In parallel, patient characteristics in the ICU were collected.Results: 24 and 23 critically ill COVID-19 patients were treated during both observation periods in April/May and November/December 2020, respectively. 87.5% and 78.2% of patients had moderate to severe acute respiratory distress syndrome. From March 6, 2020 onwards, the hospital had switched to a command and control-based hospital incident command system (HICS) and increased work forces. Point prevalence of depression-like symptoms (13.6% and 12.8%) and burnout (21.6% and 17.4%) in the department's healthcare professionals was high. Exposure to SARS-CoV-2 did not increase psychological burden. Consequences of the lockdown were rated as highly distressing by a majority of all ICU personnel. High self-reported trait resilience was protective against signs of depression, generalized anxiety, and burnout.Conclusions: During the pandemic, healthcare professionals have been suffering from increased psychological distress compared to reference data for both the general population and ICU personnel. General effects of the lockdown appear more relevant than actual COVID-19 patient contact. High trait resilience has a protective effect, yet vulnerable individuals may require specific support. Prevention against potential after effects of the lockdown, and in particular measures allowing to avoid another lockdown, appear warranted.Hintergrund: Die Studie hatte zum Ziel, die psychische Gesundheit der anästhesiologischen Mitarbeiterinnen und Mitarbeiter einer Universitätsklinik mit einer auf COVID-19 spezialisierten Intensivstation während der ersten beiden Wellen der Pandemie im Frühjahr und Herbst 2020 zu untersuchen und sowohl Risikofaktoren als auch protektive Faktoren zu identifizieren.Methoden: Es wurde eine monozentrische, Web-basierte Umfrage unter medizinischen Angestellten der Klinik für Anästhesiologie, Universitätsklinikum Würzburg, durchgeführt. Hierzu wurden validierte Tests zu den Domänen Depressivität, Ängstlichkeit, somatoforme Störungen, Burnout, Resilienz und Selbstmanagement verwendet und des Weiteren offene Fragen zu subjektiv belastenden, COVID-19-assoziierten Faktoren gestellt. Zusätzlich wurden Charakteristika der in den Umfragezeiträumen behandelten Patientinnen und Patienten sowie Informationen zum Krankenhausmanagement während der Pandemie erfasst.Ergebnisse: In den beiden Erhebungszeiträumen wurden 24 bzw. 23 kritisch kranke COVID-19-Patientinnen und -Patienten behandelt. 87.5% bzw. 78.2% der Patientinnen und Patienten litten an einer moderaten bis schweren Form des adulten akuten Lungenversagens. Ab dem 6. März 2020 implementierte die Klinik eine streng hierarchische Notfall-Einsatzleitung, um tagesaktuell auf die Dynamik der Pandemie reagieren zu können, und die personellen Ressourcen wurden erhöht. Punktprävalenzen von Depressivität (13,6% und 12.8%) und Burnout (21,3% und 17.4%) bei den Studienteilnehmerinnen und -teilnehmern waren hoch. Die unmittelbare psychische Belastung war unabhängig von einer Exposition gegenüber SARS-CoV-2. Die Auswirkungen der Ausgangsbeschränkungen wurden von einer Mehrheit der Untersuchten als stark beeinträchtigend beschrieben. Hohe Resilienz schien protektiv zu wirken gegen Anzeichen von Depressivität, generalisierter Angst und Burnout.Schlussfolgerungen: Im Verlauf der ersten Monate der Pandemie litt das medizinische Personal unter erhöhter psychischer Belastung verglichen mit früheren Vergleichsdaten sowohl der Allgemeinbevölkerung als auch von Personal auf Intensivstationen. Die allgemeinen Auswirkungen der Ausgangsbeschränkungen schienen hierbei einen größeren Einfluss gehabt zu haben als der tatsächliche Kontakt mit COVID-19-Patientinnen und -Patienten. Ausgeprägte Resilienz hatte einen positiven Effekt. Allerdings könnten anfällige Mitarbeiterinnen und Mitarbeiter unter Umständen gezielte Unterstützung benötigen. Zudem sind vorbeugende Maßnahmen gegen mögliche Nachwirkungen der Pandemie-Beschränkungen sowie alle Maßnahmen, die geeignet erscheinen, einen weiteren Lockdown zu verhindern, sinnvoll