Microglia are brain-resident immune cells. One of the many things that makes them special is that, under normal conditions, the brain and the spinal cord are closed off from the immune system. Thus, whereas the rest of our body has many innate and adaptive immune mechanisms for protection, microglia are the primary first responders and defense cells of the brain.
We have previously demonstrated that the key lysosomal transcription factors, Tfeb and Tfe3, activate lysosomal pathways in microglia and macrophages specifically in response to extracellular stress in zebrafish. Our findings question the established view that these transcription factors are required for basal lysosomal activity and reveal mechanisms using which macrophages can turn on endolysosomal signaling when challenged with immunological triggers. Our observation that macrophages have a dedicated, conserved signaling pathway to deploy lysosomal activation in response to stress led us to investigate the molecular mechanisms using which macrophages sense a wide range of environmental stress cues and transmit them to lysosomes. We believe that a broad understanding of how brain and peripheral macrophages respond to stress in vivo will be important to enhance our knowledge of infection, repair, aging, and other processes that hinge upon macrophage stress responses.
Although multiple cell types are equipped with the ability to perform phagocytosis in invertebrates, in vertebrates, this indispensable task is delegated to the professional phagocytes, including microglia and macrophages. Indeed, it has been shown that circulating monocytes, the progenitors of tissue-resident macrophages, have limited phagocytic capacity, thus indicating that the ability to phagocytose is acquired during development and through differentiation. We are fascinated by multiple open-ended questions in the field of phagocytosis: Are there molecular signals that are necessary and sufficient to endow phagocytic capacity to cells? Is the endolysosomal cascade conserved between phagocytic and non-phagocytic cell populations? Do non-professional phagocytes, such as epithelial cells, lose their phagocytic potential as development progresses? What are the “find-me”, “eat-me”, and “don’t-eat-me signals” in play during “phagoptosis” (cell death by phagocytosis), and how is this delicate process regulated?
As the primary defense, immune, and phagocytic cells in the brain, microglia govern multiple aspects of brain development, repair, and aging. In recent years, there has been an increasing appreciation of the contributions of microglia in neurodegenerative, neurodevelopmental, and neuropsychiatric disorders. In particular, the aberrant activation and resolution of microglial responses have been linked to the pathology observed in sporadic or late-onset Alzheimer’s disease. Although genome-wide association studies have revealed a number of genes potentially associated with increased risk of Alzheimer’s disease, and enriched in microglia, large-scale functional analyses of these genes have not been performed to date.
Lysosomal storage disorders (LSDs) result from defects in lysosomal catabolism and frequently present as pediatric neurodegenerative conditions. Mounting evidence suggests that inappropriate activation of innate immune cells actively contributes to the pathology in LSDs, strikingly similar to the reactive microgliosis observed in adult neurodegenerative conditions, such as Alzheimer’s disease. Despite observations indicating that aberrant activation of the immune system is an early event in many LSDs, and treatments such as bone marrow transplants or immunosuppression can be effective for some LSDs, the specific ways in which microglia and macrophages influence the onset or progression of these devastating pediatric diseases have not been thoroughly investigated.
