Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension

Bi, Qianqian; Wang, Chao; Cheng, Guodong; Chen, Ningting; Wei, Bo; Liu, Xiaoli; Li, Li; Cheng, Lü; He, Jian; Weng, Yuancheng; Yin, Chunyou; Lin, Yunfan; Wan, Shu; Li, Zhao; Xu, Jiaxi; Wang, Yi; Gu, Yan; Shen, Xiao Z.; Shi, Peng

doi:10.1016/j.immuni.2022.06.018

Cited by 29 publications

(23 citation statements)

References 115 publications

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“…AMP is converted into adenosine by CD73 and subsequently suppresses neuronal responses (40). Additionally, the "resting" microglia prevent sympathetic overactivation by maintaining Kv4.3 (a potassium channel) on presympathetic neurons (47).…”

Section: Microglia and Neurons Coordinate Cns Homeostasismentioning

confidence: 99%

The crosstalk between parenchymal cells and macrophages: A keeper of tissue homeostasis

Chen

2022

Front. Immunol.

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Non-parenchymal cells (NPCs) and parenchymal cells (PCs) collectively perform tissue-specific functions. PCs play significant roles and continuously adjust the intrinsic functions and metabolism of organs. Tissue-resident macrophages (TRMs) are crucial members of native NPCs in tissues and are essential for immune defense, tissue repair and development, and homeostasis maintenance. As a plastic-phenotypic and prevalent cluster of NPCs, TRMs dynamically assist PCs in functioning by producing cytokines, inflammatory and anti-inflammatory signals, growth factors, and proteolytic enzymes. Furthermore, the PCs of tissues modulate the functional activity and polarization of TRMs. Dysregulation of the PC‐TRM crosstalk axis profoundly impacts many essential physiological functions, including synaptogenesis, gastrointestinal motility and secretion, cardiac pulsation, gas exchange, blood filtration, and metabolic homeostasis. This review focuses on the PC‐TRM crosstalk in mammalian vital tissues, along with their interactions with tissue homeostasis maintenance and disorders. Thus, this review highlights the fundamental biological significance of the regulatory network of PC‐TRM in tissue homeostasis.

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Section: Microglia and Neurons Coordinate Cns Homeostasismentioning

confidence: 99%

The crosstalk between parenchymal cells and macrophages: A keeper of tissue homeostasis

Chen

2022

Front. Immunol.

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“…Microglia are the dominant immune cells in the parenchyma of the CNS. Many studies including ours unravel that microglia could directly modulate neuronal activities via various mechanisms in different brain regions 24–29 . Indeed, microglia activation constitutes a pivotal component of the neuroinflammation associated with hypertension 4, 6 .…”

Section: Introductionmentioning

confidence: 99%

PVN microglia via P2Y₁₂transmit hemodynamic signal to promote sympathetic excitation in hypertension

Wei,

Cheng,

et al. 2023

Preprint

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Hypertension is usually accompanied with an elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent advances reveal that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the hypothalamic paraventricular nucleus (PVN) were early responders to hypertensive challenges. PVN is the central hub for maintaining cardiovascular function via regulation of fluid balance and sympathetic outflow. Comprehensive vasculature analyses unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology among brain regions. As such, PVN is susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. ATP ligation to microglial P2Y12 receptor is responsible for the microglial accumulation and activation in the PVN. Furthermore, either pharmacological blockade or genetic ablation of microglial P2Y12 could substantially restrain blood pressure increase under hypertensive challenge. Together, these findings disclose that a unique vasculature pattern results in the vulnerability of PVN pre-sympathetic neurons to hypertension-associated insults, which is mediated by microglia.

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“…Microglia are the major source of several inflammatory mediators that drive central sensitization in the central nervous system 21–24 . Recent studies have indicated that microglia release platelet‐derived growth factor B, which promotes neuronal potassium currents via PDGFRα 25 . Microglia‐derived IL‐1β regulates neuron activity and facilitates insulin release 26 .…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23][24] Recent studies have indicated that microglia release platelet-derived growth factor B, which promotes neuronal potassium currents via PDGFRα. 25 Microglia-derived IL-1β regulates neuron activity and facilitates insulin release. 26 However, whether microglia-neuron interactions contribute to itch remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Microglia–neuron interactions promote chronic itch via the NLRP3‐IL‐1β‐GRPR axis

Liu

Wang

Zeng

et al. 2023

Allergy

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Background Spinal astrocytes contribute to chronic itch via sensitization of itch‐specific neurons expressing gastrin‐releasing peptide receptor (GRPR). However, whether microglia–neuron interactions contribute to itch remains unclear. In this study, we aimed to explore how microglia interact with GRPR+ neurons and promote chronic itch. Methods RNA sequencing, quantitative real‐time PCR, western blot, immunohistochemistry, RNAscope ISH, pharmacologic and genetic approaches were performed to examine the roles of spinal NLRP3 (The NOD‐like receptor family, pyrin‐containing domain 3) inflammasome activation and IL‐1β‐IL1R1 signaling in chronic itch. Grpr‐eGFP and Grpr KO mice were used to investigate microglia–GRPR+ neuron interactions. Results We observed NLRP3 inflammasome activation and IL‐1β production in spinal microglia under chronic itch conditions. Blockade of microglial activation and the NLRP3/caspase‐1/IL‐1β axis attenuated chronic itch and neuronal activation. Type 1 IL‐1 receptor (IL‐1R1) was expressed in GRPR+ neurons, which are essential for the development of chronic itch. Our studies also find that IL‐1β+ microglia are localized in close proximity to GRPR+ neurons. Consistently, intrathecal injection of IL1R1 antagonist or exogenous IL‐1β indicate that the IL‐1β‐IL‐1R1 signaling pathway enhanced the activation of GRPR+ neurons. Furthermore, our results demonstrate that the microglial NLRP3/caspase‐1/IL‐1β axis contributes to several different chronic itches triggered by small molecules and protein allergens from the environment and drugs. Conclusion Our findings reveal a previously unknown mechanism in which microglia enhances the activation of GRPR+ neurons through the NLRP3/caspase‐1/IL‐1β/IL1R1 axis. These results will provide new insights into the pathophysiology of pruritus and novel therapeutic strategies for patients with chronic itch.

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Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension

Cited by 29 publications

References 115 publications

The crosstalk between parenchymal cells and macrophages: A keeper of tissue homeostasis

The crosstalk between parenchymal cells and macrophages: A keeper of tissue homeostasis

PVN microglia via P2Y₁₂transmit hemodynamic signal to promote sympathetic excitation in hypertension

Microglia–neuron interactions promote chronic itch via the NLRP3‐IL‐1β‐GRPR axis

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Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension

Cited by 29 publications

References 115 publications

The crosstalk between parenchymal cells and macrophages: A keeper of tissue homeostasis

The crosstalk between parenchymal cells and macrophages: A keeper of tissue homeostasis

PVN microglia via P2Y12transmit hemodynamic signal to promote sympathetic excitation in hypertension

Microglia–neuron interactions promote chronic itch via the NLRP3‐IL‐1β‐GRPR axis

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PVN microglia via P2Y₁₂transmit hemodynamic signal to promote sympathetic excitation in hypertension