Perinatal arterial stroke is one of the main causes of cerebral palsy. The immaturity of the brain in the early postnatal period increases its susceptibility to ischemic and inflammatory damage. For a long time, microglial cells were considered to be purely injurious after neonatal brain ischemia. However, work by us and others has shown that the microglial phenotypes are diverse after neonatal injury and that the balance between the cytotoxic and protective microglia may modulate injury. The scavenger receptor CD36 plays a dual role in cerebrovascular injury. CD36 can injure by triggering oxidative stress and inflammation but can protect by cleaning up neuronal debris through phagocytosis or by altering the macrophage phenotype after injury. While genetic deletion of CD36 protects the adult brain by reducing local inflammation after middle cerebral artery occlusion (MCAO), the lack of CD36 in the neonatal brain aggravates injury after acute MCAO and affects intracellular pro- inflammatory signaling differentially than in the adult. CD36-mediated effects are ligand- specific and context-dependent, and in part depend on partnering with particular Toll-like receptors (TLR). We hypothesize that CD36 ameliorates injury after neonatal stroke by altering the balance between the cytotoxic and protective microglia in a TLR2-dependent manner. We will first determine the effect of disrupted CD36 signaling (genetic deletion, pharmacological inhibition) after neonatal MCAO on the microglial phenotypes, both cytotoxic and protective and then examine the effects of CD36 inhibition on the chemotactic activity of microglia using two-photon imaging in living injured neonatal mice (Aim 1). To determine if CD36 acts through TLR2 to modify injury, we will monitor TLR2 by bioluminescence imaging in living neonatal luc/GFP-TLR2 and CD36ko-luc/GFP-TLR2 mice subjected to MCAO or, alternatively, by stimulating microglia in living neonatal mice in both a TLR2-dependent and -independent manner (Aim 2). Finally, we will determine the effects of a lack/inhibition of CD36 on Lyn-mediated intracellular signaling in cultured microglia and the effects of altered CD36/Lyn signaling on injured cultured neurons (Aim 3).

Public Health Relevance

Stroke in the term newborn occurs in 1 in 4,000 live births. Most of these infants survive with significant long-term disabilities, and there are no treatments available to ameliorate their sufering and decrease the enormous cost to families and society. The mechanisms of ischemic brain injury in the neonate are stil inadequately studied, and targets for treatment have not been identified.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Mallard, Carina; Ek, C Joakim; Vexler, Zinaida S (2018) The myth of the immature barrier systems in the developing brain: role in perinatal brain injury. J Physiol 596:5655-5664
Mallard, Carina; Tremblay, Marie-Eve; Vexler, Zinaida S (2018) Microglia and Neonatal Brain Injury. Neuroscience :
Chip, Sophorn; Fernández-López, David; Li, Fan et al. (2017) Genetic deletion of galectin-3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke. Brain Behav Immun 60:270-281
van Velthoven, Cindy T; Dzietko, Mark; Wendland, Michael F et al. (2017) Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. J Neurosci Res 95:1225-1236
Lalancette-Hébert, Melanie; Faustino, Joel; Thammisetty, Sai Sampath et al. (2017) Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection. Brain Behav Immun 65:312-327
Bosetti, Francesca; Galis, Zorina S; Bynoe, Margaret S et al. (2016) ""Small Blood Vessels: Big Health Problems?"": Scientific Recommendations of the National Institutes of Health Workshop. J Am Heart Assoc 5:
Fernández-López, David; Faustino, Joel; Klibanov, Alexander L et al. (2016) Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke. J Neurosci 36:2881-93
Li, Fan; Faustino, Joel; Woo, Moon-Sook et al. (2015) Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke. J Neurochem 135:445-52
Mallard, Carina; Vexler, Zinaida S (2015) Modeling Ischemia in the Immature Brain: How Translational Are Animal Models? Stroke 46:3006-11
Titomanlio, Luigi; Fernández-López, David; Manganozzi, Lucilla et al. (2015) Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models. Pediatr Neurol 52:566-584

Showing the most recent 10 out of 38 publications