Bone marrow is the hematopoietic organ of adults, giving rise to all immune cells in our body. Meanwhile, as a central immune organ, bone marrow is also actively involved in the body's response to infection, injury, metabolic abnormalities, and aging, etc. Our previous work demonstrated the role of bone marrow immune responses in driving neuroinflammation in chronic brain injuries such as multiple sclerosis, and acute brain injury like stroke. These works provide us new insights into the origination of neuroinflammation. We will further explore the neural regulatory mechanism of bone marrow immunity.

2. Neurodegeneration of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system and the most common cause of disability among young adults worldwide. Autoreactive immune cells-mediated relapses and sustained neurodegeneration are two major challenges MS patients facing. Up to now, drugs that inhibit lymphocyte activation or migration can effectively control relapses, but still little is known about the driving force of neurodegeneration in MS, nor effective intervention. Compartmentalized chronic neuroinflammation is believed to be the key cause of MS degeneration, but the mechanisms driving which is still unclear and the roles of different immune cells remain to be defined.

Infection is a common complication of stroke, and stroke-related infections have a high incidence (21-65%) and mortality (~20%). Among them, the incidence of stroke-associated pneumonia (SAP) is around 10-28%, which is the most common stroke complication. SAP directly aggravates neurological deficit and mortality of stroke patients. However, effective approaches to precent SAP is still lacking. Two large randomized controlled clinical trials (PASS, STROKE-IFN) based on the European population completed in 2015 failed to confirm the effectiveness of prophylactic antibiotics in reducing SAP and improving 3-month neurological function. There is an urgent need to reconsider the mechanism underlying SAP. Stroke induces profound impacts on peripheral organs and immune system, we will try to explore the mechanisms of SAP from the perspective of the impact of brain injury on the peripheral immune system.

• Patients with multiple sclerosis exhibit prominent bone marrow myelopoiesis.
• Autoreactive T cells migrate into the bone marrow via the CXCL12-CXCR4 axis.
• Autoreactive T cells augment bone marrow myelopoiesis via CCL5-CCR5 axis.
• Bone marrow output of myeloid cells exacerbates CNS inflammatory injury

Figure 1. Bone marrow responses drive neuroinflammation of MS.

2. Revealing tPA-mobilized neutrophil migration as a mechanism underlying thrombolysis-related hemorrhage in ischemic stroke ( Circulation Research, 2021 )

Intravenous thrombolysis with tissue plasminogen activator (tPA) is the only approved pharmacological treatment in the acute phase of ischemic stroke, while the narrow time window (4.5 hours) and hemorrhagic transformation risk limit its clinical application widespread. We found that as fast as 1 hour after ischemic stroke patients receiving intravenous tPA thrombolysis, circulating neutrophils and T lymphocytes rapidly increased. Further investigation found that tPA can directly act on Annexin 2 expressed on immune cells and promote their migration into the brain, aggravating blood-brain barrier damage and hemorrhagic transformation. Combining intravenous thrombolysis and immune intervention thus represents an appealing approach to reduce the risk of hemorrhagic transformation after thrombolysis in ischemic stroke.

Figure 2. tPA mobilizes immune cells that exacerbate hemorrhagic transformation of ischemic stroke.

3. Characterizing the origination and outcome of neuroinflammation at different stages of acute brain injury ( Lancet Neurol, 2019, Cell Mol Immunol, 2019; Sci Transl Medi, 2021; J Cereb Blood Flow Metab 2022 )

Acute brain injury caused by stroke can quickly orchestrate the immune system, activate microglia, and recruit a large number of peripheral immune cells into the brain, causing secondary brain injury. Subsequently, brain injury switch peripheral immune system from competent to suppression through sympathetic and humoral pathways, manifested by lymphopenia and atrophy of immune organs such as the spleen, leading to increased risk of infections. Two clinical studies based on this finding are currently recruiting (POSITION, NCT05375240; PROCHASE, NCT05419193), aiming to verify whether post-stroke immunosuppression can be reversed and the risk of infection can be reduced by blocking the sympathetic nervous system. In the chronic phase, neuroinflammation persists in the brain and spreads throughout the brain, we termed which global brain inflammation. Global brain inflammation might continuously shape the evolving pathology after a stroke and affect the long-term neurological outcome.

Figure 3. Mechanisms of global brain inflammation post stroke.