Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) characterized by cortical demyelinating lesions containing activated microglia and phagocytic macrophages. The complex dynamics between microglia and oligodendrocytes during demyelination remain to be established. Bruton’s Tyrosine Kinase (BTK) is a key regulator of microglial phagocytosis; however, it is unclear whether modulation of BTK directly affects immune-mediated demyelination.
To visualize and manipulate in vivo microglia-oligodendrocyte interactions during cortical myelin loss and repair.
We developed a novel in vivo model of immune-mediated cortical demyelination through the application of recombinant antibodies derived from MS patients and human complement (MSrAb+huC’) onto the cortical surface. We characterized cellular interactions in real-time via longitudinal in vivo two-photon microscopy of myelinating oligodendrocytes and microglia in transgenic mice.
We found that MSrAb+huC’ application resulted in robust demyelination that recapitulated MS pathology. Microglia rapidly engulfed myelin sheaths following the application of MSrAb+huC’, and subsequently increased their density, accumulating around heavily affected oligodendrocytes. Oral administration of a brain-penetrant BTK-inhibitor prior to the application of MSrAb+huC’ drastically altered microglia dynamics in the 72 hours post-surgery, notably by diminishing engulfment morphology and density changes. Moreover, BTK-inhibition prevented the loss of oligodendrocytes.
Inhibition of BTK signaling alters microglia-oligodendrocyte interactions and limits complement-dependent antibody-mediated demyelination. These findings provide a novel context to define glial interactions during immune-regulated demyelination and outline a crucial role for microglia in driving myelin loss.