Research ArticleBRAIN INJURY

Brain injury instructs bone marrow cellular lineage destination to reduce neuroinflammation

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Science Translational Medicine  14 Apr 2021:
Vol. 13, Issue 589, eabc7029
DOI: 10.1126/scitranslmed.abc7029

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Promoting neuroimmune interaction after ICH

In patients with intracerebral hemorrhage (ICH), circulating myeloid cells increase and peripheral immune cells infiltrate into the brain parenchyma. The mechanisms mediating the increased production of monocytes and their influence on ICH remain to be elucidated. Here, Shi et al. showed that bone marrow hematopoietic stem cells (HSCs) increased in patients with ICH and in a mouse model. In mice, adrenergic innervation mediated the increased hematopoiesis after ICH and the newly produced cells infiltrating the brain suppressed neuroinflammation and reduced brain damage. Increasing the adrenergic signaling exerted therapeutic effects in mice. The results suggest that targeting the adrenergic system might be effective to curb neuroinflammation after ICH.

Abstract

Acute brain injury mobilizes circulating leukocytes to transmigrate into the perivascular space and brain parenchyma. This process amplifies neural injury. Bone marrow hematopoiesis replenishes the exhausted peripheral leukocyte pools. However, it is not known whether brain injury influences the development of bone marrow lineages and how altered hematopoietic cell lineages affect neurological outcome. Here, we showed that bone marrow hematopoietic stem cells (HSCs) can be swiftly skewed toward the myeloid lineage in patients with intracerebral hemorrhage (ICH) and experimental ICH models. Lineage tracing revealed a predominantly augmented hematopoiesis of Ly6Clow monocytes infiltrating the ICH brain, where they generated alternatively activated macrophages and suppressed neuroinflammation and brain injury. The ICH brain uses β3-adrenergic innervation that involves cell division cycle 42 to promote bone marrow hematopoiesis of Ly6Clow monocytes, which could be further potentiated by the U.S. Food and Drug Administration–approved β3-adrenergic agonist mirabegron. Our results suggest that brain injury modulates HSC lineage development to curb distal brain inflammation, implicating the bone marrow as a unique niche for self-protective neuroimmune interaction that might be exploited to obtain therapeutic effects.

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