Immune-Neurovascular Interactions in Stroke – Effects of CNS immaturity.
To unravel how brain maturation at the time of ischemic stroke affects the pathophysiology both short-term and long-term outcomes we pioneered the in vivo models of perinatal arterial ischemic stroke (PAIS) in rats and mice (Neurosci Res, 1998; Stroke, 2003; Ann Neurol, 2012) and models of childhood arterial ischemic stroke (CAIS) (JCBFM 2019) and a model of viral mimetic-induced arteriopathy of childhood (JCBFM 2021). These age-appropriate models allowed us to make major conceptual discoveries of how stroke pathophysiology depends on the maturation of the CNS and of the immune system. My lab discovered that both the structural and functional aspects of the blood-brain barrier (BBB) are markedly more intact after acute neonatal focal stroke than after adult focal stroke (J.Neurosci, 2012).
We were the first to challenge the dogma that microglial cells are toxic after stroke and that, in fact, microglia support endogenous defense mechanisms, protect BBB integrity and prevent hemorrhages from occurring
(J.Neurosci, 2011 & 2016).
Pharmacological depletion of microglia by intracortical clodronate-liposome delivery increases BBB leakage and induces parenchymal hemorrhages
Inhibition of TGFbeta signaling in microglia (ALK5-encorporated liposome injection) increases BBB leakage and parenchymal hemorrhages
We significantly advanced the mechanistic understanding of the neuroinflammatory mechanisms in injured neonatal brain, including the role of the scavenger receptor CD36 (J.Neurosci, 2020 & 2021; J.Neuroinflam, 2022), Galectin-3 (BBI, 2017), Toll-like receptor 2 (BBI, 2017; J.Neuroinflam, 2022), and S1PR2 (iScience, 2023). We identified that Omega-3 enriched diet during gestation and early postnatal protects by muting neuroinflammation induced by PAIS (Transl. Stroke Res, 2022) or endotoxin infection (J.Neuroinflam, 2024). We established how blood-CSF barrier modulates PAIS injury (J.Neurosci, 2020; J.Neuroinflam, 2022).
Recently accomplished and ongoing projects:
The role of microglia-derived exosomes (Exo) in PAIS.
We demonstrated enhanced long-term recovery from stroke by altering local brain microenvironment by mesenchyme stem cells (MSC) (Neurosci Res, 2017) and that MSC-derived Exo mimic beneficial effects of MSC administration (Neurotherapeutics, 2021), suggesting that MSC-Exo may be a safer option for PAIS than administration of MSC themselves. We demonstrated that vesicles derived from activated microglia obtained from neonatal brain after stroke modulate microglial function in vitro (Neurobiol Dis, 2021). Administration of microglia-derived Exo, not microvesicles, limits cytokine accumulation and protects from PAIS (unpublished).
The mechanisms of CAIS.
PAIS and CAIS are diseases with distinct occurrence and recurrence rates and many non-overlapping injury mechanisms dependent on the maturation of the CNS and the immune system. In juvenile mice, we developed models of CAIS (JCBFM, 2019) and viral infection-induced childhood arteriopathy (JCBFM, 2021), a known CAIS trigger. We established distinct contribution of peripheral leukocytes into injury in CAIS and identified more prominent role of neutrophils—via central role of NETosis. We examine if inhibition of neutrophil elastase/NETosis is effective in CAIS.
Adverse effects of late recanalization after PAIS and CAIS.
Prolongation of MCAO followed by reperfusion leads to a major exacerbation of the inflammatory response during acute injury in both neonatal and juvenile mice, but the magnitude of response depends on brain maturation at the time of injury and is not uniform for individual injurious pathways. We examine how interactions between monocytes and neutrophils contribute to different susceptibility of neonatal and juvenile brain to late reperfusion.