Abstract
Macrophages are the first line of defense against invading pathogens. However, exposure to prolonged hyperoxia compromises their ability to phagocytose and kill bacteria. Exposure to prolonged hyperoxia (≥95% O2) leads to the release of nuclear HMGB1 into the extracellular milieu, where HMGB1 acts as a potent proinflammatory cytokine and suppresses macrophage’s functions (2). The vagus nerve of the autonomous nervous system regulates the secretion of proinflammatory cytokines, thus may modulate HMGB1-mediated damage. Agonists bind to the orthosteric site of α7nAchR and at high concentrations may cause desensitization and can disrupt the endogeous tone of the receptor. Use of ago-PAM (positive allosteric modulator) of the α7nAchR can synergize and enhance orthosteric site mediated signaling without disrupting the endogenous signaling. We tested whether GAT107 (a novel ago-PAM) can (1) decrease hyperoxia-induced HMGB1 release from macrophages and (2) improve hyperoxia-compromised macrophage phagocytosis. RAW 264.7 cells, a macrophage like cell line, were exposed to different concentrations of GAT107 prior to exposure to 95% O2. The results show that GAT107 at trace concentrations (1.1 and 3.3μM) improved hyperoxia-compromised phagocytic ability of macrophages. In addition, at the same concentrations it effectively inhibits oxidative stress-induced release of nuclear HMGB1 to the extracellular milieu at concentrations that are non-toxic to the cells. These data indicate that GAT107 can improve hyperoxia-compromised phagocytosis via inhibiting nuclear HMGB1 release into the extracellular milieu. Therefore, targeting α7nAchR using GAT107 may be a possible novel pharmacological agent that can be used to mediate proinflammatory reflex in macrophages.
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