Background: Microglia derived VEGF-B and TGF-α are controlled by the central nervous system micro-environment and act on astrocytes and central nervous system infiltrating immune cells as opposing factors in control of lesion reversibility.
Hypothesis: Inflammation and hypoxia inversely define the balance of VEGF-B to TGF-α, a novel checkpoint of lesion reversibility with translational potential for MS and stroke.
Strategy: Determine the relevance of VEGF-B and TGF-α in inflammatory and hypoxic central nervous system diseases, modulate their balance in therapeutic in vivo models, and determine their relevance as novel biomarkers in Multiple Sclerosis and stroke.
After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes and infiltrating immune cells controls the resolution or chronification of tissue damage. Depending on polarizing factors provided by microglia, astrocytes and infiltrating immune cells either promote or inhibit this recovery process. We have demonstrated that the aryl hydrocarbon receptor (AHR) enhances the expression of TGF-α and inhibits the expression of VEGF-B in microglia, which induce or inhibit recovery, respectively. Our studies also suggest that inflammatory conditions cause a relative preponderance of microglial VEGF-B over TGF-α inhibiting lesion reversibility by acting on astrocytes and CNS infiltrating immune cells. Conversely, our new data highlight that a hypoxic micro-environment counter-regulates the microglial VEGF-B to TGF-α ratio, inducing regenerative astrocyte phenotypes favouring lesion resolution. Thus, the AHR / VEGF-B / TGF-α axis represents a novel checkpoint of lesion reversibility, which may possess therapeutic potential and significance as a novel biomarker in inflammatory and ischemic CNS diseases. Our specific aims are:
Aim ❶ How is the VEGF-B / TGF-α balance regulated during inflammation and hypoxia?
Our data show that the AHR-controlled balance between VEGF-B/TGF-α governs regenerative mechanisms in response to inflammatory and hypoxic conditions in the CNS. We propose to characterize the balance of microglia-derived VEGF-B and TGF-α for recovery in Experimental Autoimmune Encephalomyelitis (EAE) and ischemic stroke as a novel checkpoint for lesion reversibility and validate the cellular responder populations of microglial VEGF-B and TGF-α.
Aim ❷ Can we target AHR and TGF-α signalling to improve recovery in experimental autoimmune encephalomyelitis and stroke?
We have shown that AHR induces the production of protective TGF-α in microglia, while it limits disease-promoting VEGF-B. Indoxyl-3-sulfate (I3S) is a microbiome-derived AHR ligand that crosses the blood-brain barrier (BBB) and ameliorates EAE. We propose to utilize the AHR/TGF-α axis by nasally administered TGF-α and I3S to improve recovery from EAE and ischemic stroke.
Aim ❸ Are AHR ligands, TGF-α and VEGF-B novel biomarkers in MS and stroke?
We have previously demonstrated that AHR ligand levels are decreased in Multiple Sclerosis (MS) patients and correlate with disease stage and activity. The relevance of AHR ligand levels in ischemic stroke is not known to date. We propose to evaluate the relevance of AHR ligand levels, TGF-α and VEGF-B as novel biomarkers for lesion reversibility in MS and ischemic stroke.
