Integrin αMβ2 as a Key Regulator of the Anti-Inflammatory Cholinergic Response in Macrophages and Neutrophils.
Abstract
Inflammation underlies numerous diseases, including sepsis, rheumatoid arthritis, atherosclerosis, and diabetes, representing a significant global health burden where current anti-inflammatory therapies often prove insufficient. Recent studies emphasize the role of nervous system, particularly the vagus nerve, in regulating inflammation via the activation of cholinergic anti-inflammatory pathway. This pathway, mediated by α7-nicotinic acetylcholine receptors (α7nAChR) on leukocytes, suppresses inflammation in various tissues and organs, including the lungs, spleen, liver, and gastrointestinal tract, by inhibiting NF-κB activation and pro-inflammatory cytokine release. While α7nAChR agonists show promise, clinical trials remain inconclusive, suggesting additional contributing factors. Our previous work demonstrated α7nAChR regulation of macrophage migration via integrin αMβ2. Here, using LPS-induced endotoxemia, neutrophil swarming, macrophage migration assays, and leukocyte signaling analysis, we reveal a critical link between αMβ2 and α7nAChR beyond migration. Strikingly, the cholinergic anti-inflammatory response was abolished in integrin αM-deficient mice during endotoxemia. α7nAChR agonist (PNU-282987) treatment, protective in wild-type mice, worsened survival, characterized by increased mortality and exacerbated symptoms, in αM-deficient mice. Mechanistically, α7nAChR activation in αM-/- macrophages failed to suppress TNFα expression, highlighting αMβ2's role in α7nAChR-mediated NF-κB inhibition. Furthermore, α7nAChR activation in αM-deficient mice did not enhance macrophage recruitment or reduce neutrophil migration to the lungs during LPS-induced endotoxemia, demonstrating αMβ2's importance in α7nAChR-driven immune cell trafficking. Consistently, α7nAChR activation decreased wild-type, but not αM-deficient, neutrophil swarming towards Candida albicans via integrin αMβ2 deactivation, likely through conformational changes induced by α7nAChR signaling. These findings demonstrate a reciprocal relationship: αMβ2 contributes to cholinergic anti-inflammatory signaling, and α7nAChR stimulation modulates αMβ2-mediated leukocyte migration. These results identify integrin αMβ2 as a crucial component of α7nAChR-mediated anti-inflammatory signaling, suggesting that targeting αMβ2 in conjunction with α7nAChR may offer a more effective therapeutic strategy for inflammatory diseases, with significant implications for developing improved cholinergic anti-inflammatory therapies.
Start Time
16-4-2025 2:30 PM
End Time
16-4-2025 3:30 PM
Room Number
304
Presentation Type
Oral Presentation
Presentation Subtype
Grad/Comp Orals
Presentation Category
Health
Faculty Mentor
Valentin Yakubenko
Integrin αMβ2 as a Key Regulator of the Anti-Inflammatory Cholinergic Response in Macrophages and Neutrophils.
304
Inflammation underlies numerous diseases, including sepsis, rheumatoid arthritis, atherosclerosis, and diabetes, representing a significant global health burden where current anti-inflammatory therapies often prove insufficient. Recent studies emphasize the role of nervous system, particularly the vagus nerve, in regulating inflammation via the activation of cholinergic anti-inflammatory pathway. This pathway, mediated by α7-nicotinic acetylcholine receptors (α7nAChR) on leukocytes, suppresses inflammation in various tissues and organs, including the lungs, spleen, liver, and gastrointestinal tract, by inhibiting NF-κB activation and pro-inflammatory cytokine release. While α7nAChR agonists show promise, clinical trials remain inconclusive, suggesting additional contributing factors. Our previous work demonstrated α7nAChR regulation of macrophage migration via integrin αMβ2. Here, using LPS-induced endotoxemia, neutrophil swarming, macrophage migration assays, and leukocyte signaling analysis, we reveal a critical link between αMβ2 and α7nAChR beyond migration. Strikingly, the cholinergic anti-inflammatory response was abolished in integrin αM-deficient mice during endotoxemia. α7nAChR agonist (PNU-282987) treatment, protective in wild-type mice, worsened survival, characterized by increased mortality and exacerbated symptoms, in αM-deficient mice. Mechanistically, α7nAChR activation in αM-/- macrophages failed to suppress TNFα expression, highlighting αMβ2's role in α7nAChR-mediated NF-κB inhibition. Furthermore, α7nAChR activation in αM-deficient mice did not enhance macrophage recruitment or reduce neutrophil migration to the lungs during LPS-induced endotoxemia, demonstrating αMβ2's importance in α7nAChR-driven immune cell trafficking. Consistently, α7nAChR activation decreased wild-type, but not αM-deficient, neutrophil swarming towards Candida albicans via integrin αMβ2 deactivation, likely through conformational changes induced by α7nAChR signaling. These findings demonstrate a reciprocal relationship: αMβ2 contributes to cholinergic anti-inflammatory signaling, and α7nAChR stimulation modulates αMβ2-mediated leukocyte migration. These results identify integrin αMβ2 as a crucial component of α7nAChR-mediated anti-inflammatory signaling, suggesting that targeting αMβ2 in conjunction with α7nAChR may offer a more effective therapeutic strategy for inflammatory diseases, with significant implications for developing improved cholinergic anti-inflammatory therapies.