Publications

Preventing the neuron loss that underlies progression in multiple sclerosis remains an unmet goal, in part because the pathways of immune-mediated neuronal death are poorly understood. In the experimental autoimmune encephalomyelitis model we show that neurons accumulate DNA damage and die through parthanatos, a caspase-independent death program, and that blocking its final step of genomic fragmentation by MIF nuclease reduces both neuron loss and disease severity. This work identifies parthanatos as a key driver of neuronal death during neuroinflammation and a potential target for neuroprotection.

Meningeal inflammation is a known risk factor for the cortical gray matter damage that drives progressive multiple sclerosis, yet how it injures the underlying brain remains unclear. Using MRI-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation, we found broad activation of inflammatory pathways at sites of meningeal inflammation but only a subset of those programs, notably complement signaling and antigen presentation, penetrating into the adjacent brain parenchyma. This variable penetrance highlights candidate pathways in gray matter pathology and provides the first spatial transcriptomic map of meningeal inflammation.

The signals that trigger and shape inflammation after central nervous system injury remain poorly defined. Here we identify the nuclear alarmin IL-33, expressed by oligodendrocytes and released from damaged white matter, as an early regulator of the innate immune response that acts on astrocytes and microglia to drive chemokine production and monocyte recruitment. Mice lacking IL-33 show reduced myeloid cell infiltration and impaired recovery after injury, revealing IL-33 as a mediator of immune cell recruitment to the injured brain.