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GAT107, a Novel Alpha7 Acetylcholine Nicotinic Receptor ago-PAM, Attenuates Hyperoxia-Compromised Macrophage Phagocytic Function
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A2252 - GAT107, a Novel Alpha7 Acetylcholine Nicotinic Receptor ago-PAM, Attenuates Hyperoxia-Compromised Macrophage Phagocytic Function
Author Block: A. Gauthier1, R. Sitapara2, G. Thakur3, L. Mantell1; 1Pharmaceutical Sciences, St. John's University, Jamaica, NY, United States, 2Pulmokine Inc., Rensselaer, NY, United States, 3Pharmaceutical Sciences, Northeastern University, Boston, MA, United States.
Alveolar macrophages are the first line of defense against invading pathogens in the lung. However, exposure to prolonged hyperoxia compromises their ability to phagocytose and kill bacteria. Such exposure can also lead to the release of nuclear HMGB1 into the extracellular milieu, where HMGB1 acts as a potent pro-inflammatory cytokine and suppresses macrophage’s functions. The vagus nerve of the autonomous nervous system regulates anti-inflammatory reflex in part by macrophage α7 nicotinic acetylcholine receptors (α7nAchR), which modulate HMGB1-compromised host defense under hyperoxic conditions. Agonists of α7nAchR at high concentrations may cause desensitization and can disrupt the endogeous tone of the receptor. Ago-PAMs (positive allosteric modulator) of the α7nAchR can synergize and enhance orthosteric site mediated signaling without disrupting the endogenous signaling. In this study we tested whether GAT107 (a novel ago-PAM) can (1) improve hyperoxia-compromised macrophage phagocytosis and (2) decrease hyperoxia-induced HMGB1 release from macrophages through inhibition of NF-kappaB pathway. RAW 264.7 cells, a macrophage like cell line and murine Bone-Marrow Derived Macrophages (BMDMs), were exposed to different concentrations of GAT107 prior to exposure to 95% O2 (hyperoxia). The results show that GAT107 at concentrations of 1.1 and 3.3μM improved hyperoxia-compromised phagocytic ability of macrophages. In addition, GAT107 effectively inhibits oxidative stress-induced accumulation of HMGB1 in the extracellular milieu through reducing the activation of NF-kappaB. 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 modulate anti-inflammatory reflex in host-defense against pulmonary infection.
Author Block: A. Gauthier1, R. Sitapara2, G. Thakur3, L. Mantell1; 1Pharmaceutical Sciences, St. John's University, Jamaica, NY, United States, 2Pulmokine Inc., Rensselaer, NY, United States, 3Pharmaceutical Sciences, Northeastern University, Boston, MA, United States.
Alveolar macrophages are the first line of defense against invading pathogens in the lung. However, exposure to prolonged hyperoxia compromises their ability to phagocytose and kill bacteria. Such exposure can also lead to the release of nuclear HMGB1 into the extracellular milieu, where HMGB1 acts as a potent pro-inflammatory cytokine and suppresses macrophage’s functions. The vagus nerve of the autonomous nervous system regulates anti-inflammatory reflex in part by macrophage α7 nicotinic acetylcholine receptors (α7nAchR), which modulate HMGB1-compromised host defense under hyperoxic conditions. Agonists of α7nAchR at high concentrations may cause desensitization and can disrupt the endogeous tone of the receptor. Ago-PAMs (positive allosteric modulator) of the α7nAchR can synergize and enhance orthosteric site mediated signaling without disrupting the endogenous signaling. In this study we tested whether GAT107 (a novel ago-PAM) can (1) improve hyperoxia-compromised macrophage phagocytosis and (2) decrease hyperoxia-induced HMGB1 release from macrophages through inhibition of NF-kappaB pathway. RAW 264.7 cells, a macrophage like cell line and murine Bone-Marrow Derived Macrophages (BMDMs), were exposed to different concentrations of GAT107 prior to exposure to 95% O2 (hyperoxia). The results show that GAT107 at concentrations of 1.1 and 3.3μM improved hyperoxia-compromised phagocytic ability of macrophages. In addition, GAT107 effectively inhibits oxidative stress-induced accumulation of HMGB1 in the extracellular milieu through reducing the activation of NF-kappaB. 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 modulate anti-inflammatory reflex in host-defense against pulmonary infection.
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