Current research directions (click to learn more)
STAT5 tetramerization in autoimmune-mediated neuroinflammation
Multiple sclerosis (MS) is an immune-mediated disease that impacts approximately 2.3 million people world- wide. MS is caused by the activation and the complex interactions between different immune cell types that cause inflammation in the central nervous system (CNS), which leads to demyelination and axonal degeneration. A validated animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), has been utilized to demonstrate that the cognate interactions between CD4+ T cells and monocyte-derived cells (MDCs) during the autoimmune-driven neuroinflammation, are required for the pathogenesis of EAE.
The overall goal of this study is to identify signaling pathways and their downstream effector mediators that regulate the interactions of CD4+ T cells and MDCs within CNS that promote the pathogenesis of EAE.
Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) play a critical role in mediating cellular responses following stimulation of cytokines, interferons, growth factors. The activated STAT5 proteins can form dimers and tetramers. The biological functions of STAT5 tetramers are not fully understood.
Using a Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, in which STAT5 tetramers cannot be formed but STAT5 dimers are unaffected, we found that STAT5 tetramers promote the pathogenesis of EAE. The mild EAE phenotype in DKI mice correlates with reduced interactions of CD4+ T cells and monocytes/MDCs in the spinal cord meninges during EAE.
Interactions between CD4+ T cells (white), monocytes (red), MDCs (yellow), and dendritic cells (green) in the spinal cord meninges during EAE progression.
We further demonstrated that STAT5 tetramer activation by cytokine GM-CSF promotes monocyte differentiation into dendritic cells and the expression of chemokine CCL17. Correspondingly, the expression of CCL17 in the spinal cords is significantly reduced in DKI mice during EAE.
Our central hypothesis is that GM-CSF-mediated STAT5 tetramerization is critical for facilitating the interactions of pathogenic Th17 cells and monocytes/MDCs in the spinal cord meninges via a CCL17-dependent mechanism, and these cell interactions are required to promote the pathogenesis of EAE.
The role of microglia in post-ischemic stroke recovery
Current treatment options for patients experienced ischemic stroke allow blood reperfusion to the brain but fails to resolve the neurological deficits, which cause long-term physical and cognitive disabilities in stroke survivors. Thus, novel therapeutic strategies for improving brain recovery and resolving neurological deficits are critically needed.
Transient middle cerebral artery occlusion (tMCAO) is an excellent mouse model to study the inflammatory response in the brain and the pathological consequences following ischemic stroke. Neuronal death induces the activation of microglia that express proinflammatory mediators, leading to the exacerbation of brain damage following ischemic stroke. Thus, targeting microglia was thought to ameliorate brain injury post-stroke. However, recent studies have shown that the elimination of microglia increases the size of brain infarct and worsens the neurological deficits of mice following tMCAO, suggesting a functional heterogeneity of microglia in response to ischemic insults, or a temporal phenotypic shift of microglia from neurotoxic to neuroprotective over time following ischemic injury.
The overall goal of this proposal is to identify molecular signaling that potentiates these diverse functions or phenotypical shift in microglia, and to determine the potential neuroprotective role of a subset of microglia in brain recovery following ischemic stroke.
During tMCAO, a filament is inserted into the external carotid artery (ECA), which is further propelled to the internal carotid artery (ICA) then to the middle cerebral artery, where the filament is left in place for 45-60 minutes. The filament is then removed and blood reperfusion is allowed to occur.
Cerebral swelling and edema in the ipsilateral (stroke) hemisphere was observed 3 days following tMCAO, and a significant tissue loss occurred in 2 weeks.
Cresyl violet staining showed a significant neuronal death in the ipsilateral hemisphere on day 3, whereas a glial scar with dense cell proliferation and infiltration was observed on day 14
Immunofluorescence staining of IBA-1 and GFAP has shown that the activated IBA-1+ microglia were found in the ipsilateral infarct area on day 3 following tMCAO, which was surrounded by the GFAP+ astrocytes. On day 14, the IBA1+ microglia were densely populated within a contracted glial scar.