Immune Quiescence of the Brain Is Set by Astroglial Connexin 43

Abstract

In the normal brain, immune cell trafficking and immune responses are strictly controlled and limited. This unique homeostatic equilibrium, also called brain immune quiescence, is crucial to maintaining proper brain functions and is altered in various pathological processes, from chronic immunopathological disorders to cognitive and psychiatric impairments. To date, the precise nature of factors regulating the brain/immune system interrelationship is poorly understood. In the present study, we demonstrate that one of these regulating factors is Connexin 43 (Cx43), a gap junction protein highly expressed by astrocytes at the blood-brain barrier (BBB) interface. We show that, by setting the activated state of cerebral endothelium, astroglial Cx43 controls immune recruitment as well as antigen presentation mechanisms in the mouse brain. Consequently, in the absence of astroglial Cx43, recruited immune cells elaborate a specific humoral autoimmune response against the von Willebrand factor A domain-containing protein 5a, an extracellular matrix protein of the brain. Altogether, our results demonstrate that Cx43 is a new astroglial factor promoting the immune quiescence of the brain.

Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

“…Intriguingly, Boulay et al . recently reported that astroglial Cx43 controls immune cell recruitment43. Thus, downregulation of astrocytic Cx43 may promote infiltration of immune cells into brain parenchyma and propagate inflammatory reactions, especially in the presence of proinflammatory cytokines and chemokines produced by activated microglia, as shown by the current and previous studies4445.…”

Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface

“…Among the endfeetome, we found molecules already known to control cerebrovascular functions such as Cx43 (Gja1), which is implicated in BBB immune quiescence [8, 34], Agt, which plays a role in BBB integrity [35], or Aqp4, Kir4.1 (Kncj10), Hepacam and Mlc1, which are all involved in perivascular homeostasis [13, 30, 36]. Their presence strongly suggested that the endfeetome represents important astroglial functions for the regulation of the brain vascular physiology.…”

Neural Engineering

“…They impede free exchange of solutes (Ohtsuki and Terasaki 2007 ) with the exception of lipidsoluble molecules smaller than 400 Da with less than nine hydrogen bonds, which are able to cross BBB via lipid mediated diffusion (Pardridge 2007 ). Structurally, the cells are connected to each other via tight junctions (TJs), adherens junctions (AJs) (Hawkins and Davis 2005 ), and gap junctions (Boulay et al 2015 ), which are required for the compact characteristics of the barrier. Their main role is to restrict passage of unwanted molecules between blood and brain by forming a continuous layer of membrane that does not contain fenestrae, which are normally found on the endothelial cells of blood vessels for rapid exchange of molecules.…”