Leukocytes protect against pathogens; however, these cells are also protagonists of acute and chronic diseases of the central nervous system (CNS). While the steady-state brain relies on locally sourced innate immune cells such as microglia which enables recruitment of immune cells that arise from hematopoietic organs. In particular, innate immune cells such as neutrophils and monocytes migrate to the diseased brain. These cells are produced by hematopoietic stem and progenitor cells (HSPC) in the bone marrow. Inflammatory conditions, including brain ischemia, increase the production of myeloid cells, which are subsequently recruited to the ischemic brain. Similarly, chronic inflammatory CNS disorders may lead to leukocyte recruitment. Emerging data indicate that recruited leukocytes pursue functions with high relevance to brain recovery and function. The current dogma states that in response to systemic stimuli, hematopoietic marrow homogenously releases leukocytes into the systemic circulation and that these leukocytes migrate to the injured brain via the carotid and vertebral arteries. We discovered small vascularized channels that connect the skull bone marrow with the surface of the brain. These 20m sized channels through the inner skull cortex are clad with endothelial cells and frequented by neutrophils and monocytes. Our unpublished preliminary data document that this leukocyte migration increases in inflammatory conditions. We developed imaging tools, including intravital microscopy, to interrogate cellular traffic in these channels. Here we propose to characterize this hypothetical alternative leukocyte migration route in the steady state, as a function of aging and development, after ischemic stroke and in hypertension. We will test the overarching hypothesis that small vascular channels serve as a short cut for leukocytes from skull marrow to sites of CNS inflammation. Since it is currently unknown whether the skull bone marrow functions in synchrony with the marrow in vertebrae, pelvis and long bones, or alternatively exhibits regionally unique properties that may be important due to its proximity to the brain, we will compare the function of skull marrow derived leukocytes to cells made in other hematopoietic sites in steady state, hypertension and after brain ischemia. This application unites an interdisciplinary team with expertise in neuroscience, hematology, immunology, vascular biology and imaging to investigate novel microvasculature that may connect the hematopoietic skull tissue with the dura, the CNS surface and possibly parenchyma. The gained insight may inform novel anti-inflammatory therapeutic approaches for the treatment of inflammatory CNS disorders.

Public Health Relevance

In this application, we aim to investigate the function of recently discovered microvascular channels that connect the skull marrow cavities with the surface of the central nervous system, testing the hypothesis that the channels serve as leukocyte migration routes. We further test whether the skull bone marrow, due to its proximity to the brain, serves a specific role after ischemic stroke and in hypertension.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Bosetti, Francesca
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Massachusetts General Hospital
United States
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Nahrendorf, M (2018) Myeloid cells in cardiovascular organs. J Intern Med :