Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models
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ABSTRACT:
PROVIDER: PRJNA1107583 | ENA |
REPOSITORIES: ENA
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Project description:The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. The molecular basis for this pathophysiology, however, remains incompletely understood. In this study, we demonstrated that SETDB2, a histone methyltransferase expressed in trigeminal ganglion (TG) neurons, plays a pivotal role in facilitating migraine-associated pain behaviors. We modelled chronic headache with repeated administration of nitroglycerin (NTG, a well-recognized migraine trigger in migraineurs) and observed a notable upregulation of SETDB2 in mouse TG neurons following NTG treatment. A comparable increase was also identified in the cerebrospinal fluid of migraine sufferers. Reversing the NTG-induced SETDB2 upregulation abrogated the increased trimethylation of histone H3K9 (H3K9me3) and alleviated established migraine-associated pain behaviors. Conversely, mimicking the upregulation of SETDB2 in intact TG neurons was sufficient to induce pain hypersensitivity. Moreover, we found that SETDB2 upregulation induced by NTG prevented the binding of the transcription factor KLF4 to the promoter of the insulin-degrading enzyme (Ide) gene. This, in turn, inhibited IDE expression, and hindered the degradation of calcitonin- gene-related peptide (CGRP), a promising target for preventing migraine, in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present novel therapeutic opportunities for treating migraine.
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Project description:The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. The molecular basis for this pathophysiology, however, remains incompletely understood. In this study, we demonstrated that SETDB2, a histone methyltransferase expressed in trigeminal ganglion (TG) neurons, plays a pivotal role in facilitating migraine-associated pain behaviors. We modelled chronic headache with repeated administration of nitroglycerin (NTG, a well-recognized migraine trigger in migraineurs) and observed a notable upregulation of SETDB2 in mouse TG neurons following NTG treatment. A comparable increase was also identified in the cerebrospinal fluid of migraine sufferers. Reversing the NTG-induced SETDB2 upregulation abrogated the increased trimethylation of histone H3K9 (H3K9me3) and alleviated established migraine-associated pain behaviors. Conversely, mimicking the upregulation of SETDB2 in intact TG neurons was sufficient to induce pain hypersensitivity. Moreover, we found that SETDB2 upregulation induced by NTG prevented the binding of the transcription factor KLF4 to the promoter of the insulin-degrading enzyme (Ide) gene. This, in turn, inhibited IDE expression, and hindered the degradation of calcitonin- gene-related peptide (CGRP), a promising target for preventing migraine, in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present novel therapeutic opportunities for treating migraine.
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Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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