Metabolism as a modulator of immune, neuronal, and glial function
Manipulating GAPDH and aerobic glycolysis as an anti-inflammatory strategy in autoimmune disease. In both myeloid and lymphoid cells of the immune system, pro-inflammatory signals produce a metabolic switch in energy metabolism, leading to upregulated glycolysis akin to the Warburg effect first described in cancer. Our recent work (https://science.sciencemag.org/content/360/6387/449.long) found that the immunomodulatory drug dimethyl fumarate, which is used to treat MS, acts at least in part by blocking aerobic glycolysis in activated immune cells through inactivation of the enzyme GAPDH. These findings provide proof-of-concept that metabolic pathways can be manipulated to treat diseases associated with immune dysregulation. Currently, we’re examining the mechanisms by which glycolysis inhibition modulates the immune system, as well as exploring strategies (both dietary and pharmacologic) to manipulate metabolism to produce anti-inflammatory effects.
Identifying metabolic pathways regulating inflammatory and repair activities of oligodendrocyte precursor cells (OPCs). OPCs exist throughout the CNS and repair myelin by differentiating into mature oligodendrocytes, but OPC maturation appears to be blocked in chronic MS lesions. OPCs also have many functions beyond simply serving as a source of new oligodendrocytes, however. Several exciting recent studies have shown that inflammatory cytokines block OPC maturation/differentiation and produce a distinct phenotype with characteristics similar to activated immune cells, with the ability to phagocytose myelin and cross-present antigen to T lymphocytes. Given the increasingly understood role of metabolism in both immune activation and precursor cell fate (the metabolite taurine was recently shown to enhance oligodendrocyte differentiation), we are collaborating with Dr. Pavan Bhargava’s lab (https://www.hopkinsmedicine.org/profiles/results/directory/profile/10003441/pavan-bhargava) to identify targetable metabolic pathways regulating the inflammatory and repair activities of OPCs.
Identifying pathways by which nitric oxide (NO) and other free radicals cause neuronal and axonal damage
Targeting nitrosylated GAPDH (SNO-GAPDH) to prevent inflammatory neuro-axonal injury and mitochondrial dysfunction. Previous work in the lab of Sol Snyder and others has shown that NO produces a post-translational modification of GAPDH called S-nitrosylation, and S-nitrosylated GAPDH (SNO-GAPDH) translocates to both the nucleus and mitochondria. Nuclear SNO-GAPDH has been implicated in cell death mechanisms. While effects of SNO-GAPDH on mitochondrial function have not been explored, several of its targets, such as SIRT1 and PGC-1a, play a major role in mitochondrial biogenesis and function. SNO-GAPDH is thus a likely candidate in mediating neuro-axonal injury in neuroinflammation by multiple potential mechanisms. Importantly, SNO-GAPDH signaling can be blocked by small molecules such as CGP3466, a highly specific, oral CNS-penetrant drug with an established safety profile in humans. We are currently examining the role of SNO-GAPDH signaling in mediating the effects of NO on mitochondrial bioenergetics and neuro-axonal injury in neuroinflammation.
Modulating the innate immune system in MS and other neurodegenerative diseases
Bryostatin-1 and other PKC-targeted drugs as modulators of innate immunity and remyelination in the CNS. Bryostatin-1 (bryo-1) is a naturally occurring, CNS-penetrant compound that acts as a highly potent modulator of multiple protein kinase C (PKC) isoforms. It has completed phase 2 testing in humans for cancer and Alzheimer’s disease with a favorable safety profile. In collaboration with others at Johns Hopkins, we previously found that bryo-1 has immunomodulatory properties that are most pronounced in myeloid-lineage cells, favoring a reparative M2 phenotype and producing marked benefit in experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation (https://www.pnas.org/content/115/9/2186.long). We have preliminary data that it may promote oligodendrocyte differentiation – possibly through direct effects on OPCs, indirect effects on macrophages/microglia, or both. Our current work is exploring the effects of bryo-1 and related drugs on innate immune cells in the CNS and in vivo models of remyelination and neurodegeneration.