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

Immunity. 2022 Aug 9;55(8):1466-1482.e9. doi: 10.1016/j.immuni.2022.06.018. Epub 2022 Jul 20.

Abstract

Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.

Keywords: Kcnd3; Kv4.3; PDGFR inhibitor; hypertension; hypothalamic paraventricular nucleus; microglia; paracrine action; platelet-derived growth factor B; potassium current; sympathetic nerve activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hypertension* / metabolism
  • Mice
  • Microglia*
  • Neurons / physiology
  • Potassium / metabolism
  • Proto-Oncogene Proteins c-sis / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism

Substances

  • Proto-Oncogene Proteins c-sis
  • Receptor, Platelet-Derived Growth Factor alpha
  • Potassium