B1-adrenergic blockers preserve motor function by inhibiting the production of extracellular traps

Abstract

Sepsis is characterized by a dysregulated host response to an infection, potentially leading to fatal organ dysfunctions. Among these organs, the central nervous system (CNS) is particularly affected with encephalopathies associated or not with chronic disabling pain. These symptoms are caused by broad neuroinflammation with activation of resident microglia cells and infiltration of leukocytes, especially neutrophils. These immune cells have the ability to produce extracellular traps (ETs) in blood and tissues. These components are composed of chromatins and various antimicrobial proteins, and its role is to capture and destroy pathogens. However, in case of excessive production, deleterious effects occur such as tissue damage and reduction of neuronal excitability.In this study, the objectives were: 1) to determine whether in a model of endotoxemic shock, neutrophils and microglia form ETs in the CNS; 2) and to determine if a modulation of ETs production was beneficial on neuromuscular disorders associated with endotoxemic shock.We observed an infiltration of neutrophils in the SNC, an activation of microglia and a production of ETs following intraperitoneal lipopolyssacharide (LPS) administration in mice (adult Swiss male, 30-45g). Atenolol, a β1-adrenergic blocker with intrinsic immunomodulatory properties, significantly decreases the production of ETs associated in both microglia and neutrophils (citrullinated histone H3: 279.1 ± 101.9 MFI versus 117.1 ± 77.21 MFI, p<0,01). In addition, this treatment preserved the gastrocnemius motoneurons excitability (39,93 ± 15,16 mV in control group, 8.147 ± 5.892 mV in LPS group and 27.32 ± 10.73 mV in LPS+atenolol group). Similar results have been observed when the production of ETs was prevented by using sivelestat (inhibitor of extracellular traps).In conclusion, our results demonstrate that sepsis increases neutrophil infiltration into the spinal cord, activates immune cells and produces extracellular traps that directly impair motor function. Prevention of ETs formation partly restores motor function and could be a good target in order to reduce adverse effects in sepsis but also in other motor related pathologies. This work was supported by funding from the Chancellerie des Universites de Paris (Legs Poix), INSERM and Paris-Saclay University-UVSQ. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.