Background: The immune system is critically involved in the various steps of the repair program. However, at more advanced disease stages, maladaptive inflammation arises, and consequently the regenerative response cannot occur and tissue damage increases.
Hypothesis: We propose that a maladaptive chronic immune response can be initiated when the capacity of microglia to cope with myelin debris is exceeded.
Strategy: We will pursue an integrative and multidisciplinary approach by bringing together genetics, cell biology, single cell genomics and imaging in model systems of acute and chronic models of demyelinating injury.
Summary
Demyelinating injury in the central nervous system is followed by a regenerative process, which depends on a precisely coordinated multicellular response including the function of the innate immune system. If successful, myelin sheaths are re-formed and axonal health is restored. However, its declining efficiency in demyelination diseases such as multiple sclerosis (MS) is a major contributing factor to disease progression, and hence the need to therapeutically promote remyelination is an important and so far unmet clinical goal. Previously, we have shown that in demyelinating lesions cholesterol-rich myelin debris can impair the efflux capacity of microglia/macrophages, thereby posing a barrier for tissue regeneration. We found that lipid-sensing nuclear receptor unresponsiveness in microglia/macrophages was one important checkpoint and a key underlying cause for poor regeneration. Surprisingly, when we compared the response of microglia/macrophages in acute and chronic models of demyelination, we detected fundamental differences in how phagocytes handle myelin debris phagocytosis, metabolism and efflux. Chronic demyelination resulted with time in a block of myelin debris metabolism in microglia, and led to astrocyte reactivity and adaptive immune responses. Based on these preliminary findings, we propose that a maladaptive chronic immune response can be initiated when the capacity of microglia to cope with myelin debris is exceeded. As a result, a self-propagating immune response evolves that not only result in a failure of remyelination but also in further tissue damage. Because this process has the properties of a self-amplifying positive feedback loop it has the potential to shift an acute and resolving demyelinating lesion into a chronic state. Our key goal is therefore to identify the underlying molecular checkpoints in microglia/macrophages driving this process. Specifically, and based on our preliminary data, we will test whether interferon signalling constitute such a checkpoint. We propose that progressive myelin debris accumulation triggers interferon-responsive microglia and CD8 T cell infiltration that impact astrocyte and oligodendrocyte function. To realize these aims we plan to pursue an integrative and multidisciplinary approach by bringing together genetics, cell biology, single cell genomics and imaging in model systems of acute and chronic models of demyelinating injury.
