kshi(at)cimrbj.ac.cn
Multiple Sclerosis and Related Disorders, Stroke,
Neuro-Immune Interaction, Neuroinflammation,
Bone Marrow Immunity
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The Shi laboratory at CIMR investigates the interactions between the nervous and peripheral immune systems, and their roles in the pathogenesis of central nervous system (CNS) disorders such as Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), and Stroke. Recently, the lab characterized bone marrow immune responses in MS and stroke, identifying CCL5-CCR5-mediated bone marrow myelopoiesis as a key driver of disease progression in MS. Based on this discovery, the lab co-developed a novel CCR5 inhibitor, Thioraviroc, as a new therapeutic for MS, which has been approved for conducting clinical trials as class 1 innovative drug by Chinese CDE, a phase 2 trial to test the safety and efficacy of Thioraviroc (THIRL-MS) in MS patients is now ongoing. The lab is currently focusing on deciphering the driving force of neurodegeneration in both MS and chronic stroke, aiming to reveal new therapeutic targets for slowing disease progression and to improve long-term outcome, which is an urgent yet unmet clinical challenge.
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.
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