A decade ago, the group that performed the current study, along with another research group, discovered3,4 an unexpected immunoregulatory role for a ligand-activated transcription factor called the aryl hydrocarbon receptor (AHR), which at the time was best known as a receptor for environmental toxins5. The two groups showed that AHR modulates the progression of experimental autoimmune encephalomyelitis (EAE) — an autoimmune disease in mice in which the immune system becomes overactive and attacks the CNS. EAE is often used a model of multiple sclerosis (MS). Initially, the groups focused on how AHR might affect EAE by regulating pathogenic and protective subsets of immune cells outside the CNS. But it later emerged that AHR is also strongly expressed in the CNS, particularly in microglia and astrocytes6, raising the question of whether AHR in the CNS has a role in autoimmune diseases.
In the current study, Rothhammer et al. induced EAE in mice that had been genetically engineered so that AHR could be deleted in microglia (but not in other brain cells or immune cells) by a drug treatment. Elimination of microglial AHR substantially exacerbated EAE in the AHR-depleted mice, but left immune responses outside the CNS unaltered. This finding suggests that AHR activation in microglia inhibits inflammation in the CNS.
Microglia rarely act alone. Instead, they often team up with other cell types to respond to the stimuli that activate them. For example, after being activated, microglia can instruct certain astrocytes to attack local neurons7. Rothhammer and colleagues found that AHR-deficient microglia activated by EAE triggered exaggerated inflammatory responses in local astrocytes. Next, the authors used bioinformatics to analyse the gene-expression pathways altered in these glia. This analysis suggested that unexpected proteins signal from microglia to astrocytes.
The usual suspects in such cases are pro-inflammatory signalling molecules, but Rothhammer et al. showed that AHR in microglia directly regulates the expression of genes that encode the proteins TGF-α and VEGF-B (Fig. 1) — neither of which has previously received much attention from neuroimmunologists. Subsequent detailed in vitro and in vivo analyses confirmed that TGF-α and VEGF-B regulate the pro-inflammatory reactivity of astrocytes. TGF-α dampens astrocyte inflammatory responses to EAE, and its expression in microglia is inhibited by AHR deletion. Conversely, VEGF-B enhances responses to EAE, and its expression is promoted by AHR deletion.