Novel animal model of multiple sclerosis: The glial connexin gap junction as an environmental tuner for neuroinflammation

Abstract

Connexins, which comprise gap junctions (GJs) via homotypic/heterotypic oligomerization, act as channels to connect opposing cells, mainly in solid organs such as the skin, liver, heart, and central/peripheral nervous system. Connexins are synthesized in the endoplasmic reticulum, assembled in the Golgi apparatus as hexamers, and inserted into the cell membrane as hemichannels. These hemichannels are closed under normal conditions until they combine to form clusters and connect to neighboring cells via GJs in a head‐to‐head configuration. Opening of hemichannels, which depends on the intra‐ or extracellular environment, allows various bioactive molecules to enter into or be released from the host cells. Recent pathological studies on human demyelinating diseases have revealed alterations of connexin expression patterns in demyelinating lesions. To elucidate the molecular mechanisms of connexins in the pathomechanisms of inflammatory demyelination, we induced experimental autoimmune encephalomyelitis (EAE) in connexin 30 (Cx30)‐deficient mice, oligodendroglia‐specific Cx47‐ablated mice, and astroglia‐specific Cx43‐ablated mice. We found that both astroglial‐Cx30‐deficient mice and Cx43‐ablated mice showed amelioration of the clinical course of EAE, while oligodendroglial‐Cx47‐ablated mice showed aggravation. These findings indicate the distinct role of connexins expressed in different cell types and the substantial contribution of connexin‐mediated pathology to demyelinating disorders. The imbalance in connexin expression, which is caused by the inflammatory environment, results in an increase in hemichannels in glial cells. The release of proinflammatory molecules induced by the increase in hemichannels on activated glial cells is a crucial mechanism of demyelinating disorders.

Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer’s Disease

“…In AD, neurons could release soluble neurotoxic Aβ peptides to the extracellular space, which in turn stimulate microglial cells to produce proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-a) and reactive oxygen species (ROS), leading to the activation of astrocytes around the area of the extracellular beta-amyloid plaques [ 50 , 51 , 52 ]. Reactive astrocytes respond by releasing chemokines and cytokines such as interleukin-1-beta (IL-1β), which maintain the vicious Aβ-generation cycle with neuroinflammatory and neurodegenerative consequences [ 3 , 51 , 53 ].…”

The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity

“…Although there is an apparent lack of Cx30 effect in slowing down ALS progression, this protein has an important role in regulating the inflammatory response. Cx30 deficiency increased microglia ramifications enlarged astrocytic processes, and reduced Cx43 expression [280,281]. Recent findings suggest, using a genetic approach that reduced expression of astroglial Cx30 in SOD1 G93A mice protects neurons at the early disease stage by attenuating astroglial inflammation [282] and, similarly, reducing Cx43 expression improved disease progression [283].…”

Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation

“…Reactive astrocytes have two phenotypes: an 'A1 proinflammatory phenotype induced by activated neuroinflammatory microglia, and an 'A2 neuroprotective phenotype observed after ischemic stroke [44][45][46]. To elucidate the pathogenesis of glial inflammation in neuroinflammatory diseases enacted through Cx30, we previously employed Cx30deficient mice [47,48]. Cx30 deficiency causes an increase in ramified microglia, enlargement of astrocytic processes in the spinal gray matter, and reduction of Cx43 expression in the spinal white matter.…”