AhR-deficiency as a cause of demyelinating disease and inflammation

Abstract

The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.

Lack of the aryl hydrocarbon receptor accelerates aging in mice

“…Specifically, AhR has been implicated in the myelination process in the CNS because a phenotype with an altered optic nerve myelin sheath has been described in AhR-null mice. Importantly, in the present report, demyelination was associated to an increased expression of proinflammatory cytokines (40).…”

A genome-wide CRISPR/Cas9 screen reveals that the aryl hydrocarbon receptor stimulates sphingolipid levels

“…The formation of the growing Schwann cell myelin membrane, which expands several thousand-fold during development, requires an extremely high influx of new substrate produced through the SL biosynthetic pathway, mostly in the form of hexosyl ceramide (galactosyl ceramide) (45). Previous results have shown that Ahr KO mice have thinner myelin sheaths, dysregulated myelin gene expression, and locomotor deficiencies (36,37). We confirmed this abnormally thin myelination and have now shown that some SL gene expression levels, as well as the hexosyl ceramide levels that are critical for myelin formation, are significantly reduced in actively myelinating sciatic nerves of Ahr KO mice.…”

“…Ahr deficiency in mice has been reported to cause abnormally thin myelin sheaths during development (36,37). Myelin formation is critically dependent on SL production, where SLs constitute the majority of non-sterol lipid in the expansive myelin membrane (12,38).…”

AhR signaling pathways and regulatory functions

“…Other vascular abnormalities have been observed in these mice, such as the persistence of the hyaloid artery and an impairment of limbic vascularization in the developing eye [57] . The AhR KO mice also develop an ocular pathology which consists of a horizontal pendular nystagmus which is associated with myelin defects of the optic nerve and a local inflammation [64] . Similar myelin defects also have been identified recently in the peripheral nervous system [65] .…”