Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

Yang, Dianer; Sun, Yu; Bhaumik, Siddhartha Kumar; Li, Yikun; Baumann, Jessica M.; Lin, Xiaojuan; Zhang, Yujin; Lin, Shang Hsuan; Dunn, Richard S.; Liu, Chia-Yang; Shie, Feng Shiun; Lee, Yi‐Hsuan; Wills‐Karp, Marsha; Chougnet, Claire; Kallapur, Suhas G.; Lewkowich, Ian P.; Lindquist, Diana M.; Murali‐Krishna, Kaja; Kuan, Chia Yi

doi:10.1523/jneurosci.2582-14.2014

Cited by 70 publications

(67 citation statements)

References 56 publications

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“…Notably, the exogenous TLR4 agonist, lipopolysaccharide (LPS), was the most potent stimulus for antigen-loaded macrophages to drive T H 17 polarization in human autologous co-cultures (50). Although T-lymphocytes do not routinely cross the blood-brain barrier (BBB) (51), intraperitoneal LPS administration increased the differentiation and brain influx of T H 17 cells after neonatal hypoxia-ischemia (52). T H 17 cells also comprised a larger proportion of total T-lymphocytes within the brain, as compared to blood; suggesting T H 17 cells may locally polarize and/or preferentially traffic into the CNS after TBI.…”

Section: Discussionmentioning

confidence: 99%

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

Braun

Vaibhav

Saad

et al. 2017

The Journal of Immunology

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Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurological injury over the days and weeks following a TBI. Herein, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and pro-inflammatory (M1) polarization of macrophages for up to three weeks post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naïve T lymphocytes, enhanced the polarization of T effector cells (Teff: TH1/TH17), and decreased the production of regulatory T cells (TREG) in a mixed lymphocyte reaction. Similarly, elevated Teff polarization within both blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed both M1 macrophage and TH1/TH17 polarization after TBI, as compared to C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and TH1/TH17 polarization, as compared to C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.

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Section: Discussionmentioning

confidence: 99%

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

Braun

Vaibhav

Saad

et al. 2017

The Journal of Immunology

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“…While the efficacy of T H 1/T H 17 inhibition remains unexplored after TBI, T H 17 cells drove chronic microglial polarization after EAE and co-culture studies showed myelin-specific T-lymphocytes that secreted IL-17 potently activated inflammatory cytokine expression in microglia [268, 269]. Furthermore, attenuation of brain T H 17 influx reduced white matter injury, limited brain atrophy, and prevented chronic functional deficits after neonatal hypoxia-ischemic injury [270]. These findings are in line with reports showing myelin-reactive T H 17 cells induced demyelination and impaired endogenous remyelination in pre-clinical white matter injury models and in multiple sclerosis patients [271–276].…”

Section: Translational Implicationsmentioning

confidence: 99%

“…Similarly, the TLR4 agonist, LPS, induced IL-23 expression in peritoneal macrophages via TLR4 activation [286]. Finally, HMGB1-TLR4 signaling also increased myeloid IL-23 expression and subsequent T H 17 production/mobilization after myocardial ischemia-reperfusion [287], periodontitis [288], or neonatal hypoxia-ischemia [270], although this issues remains to be fully studied after TBI. Given the temporal delay between TBI and adaptive immune responses, blocking T H polarization, secondary to DAMP-induced macrophage activation, may provide a feasible approach to limit long-term progressive injury.…”

Section: Translational Implicationsmentioning

confidence: 99%

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

Braun

Vaibhav

Saad

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Traumatic brain injury (TBI) is a leading cause of mortality and long-term morbidity worldwide. Despite decades of pre-clinical investigation, therapeutic strategies focused on acute neuroprotection failed to improve TBI outcomes. This lack of translational success has necessitated a reassessment of the optimal targets for intervention, including a heightened focus on secondary injury mechanisms. Chronic immune activation correlates with progressive neurodegeneration for decades after TBI; however, significant challenges remain in functionally and mechanistically defining immune activation after TBI. In this review, we explore the burgeoning evidence implicating the acute release of damage associated molecular patterns (DAMPs), such as adenosine 5′-triphosphate (ATP), high mobility group box protein 1 (HMGB1), S100 proteins, and hyaluronic acid in the initiation of progressive neurological injury, including white matter loss after TBI. The role that pattern recognition receptors, including toll-like receptor and purinergic receptors, play in progressive neurological injury after TBI is detailed. Finally, we provide support for the notion that resident and infiltrating macrophages are critical cellular targets linking acute DAMP release with adaptive immune responses and chronic injury after TBI. The therapeutic potential of targeting DAMPs and barriers to clinical translational, in the context of TBI patient management, are discussed.

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“…In a model of hypoxia/ischemia with systemic inflammation (lipopolysaccharide; to mimic intrauterine infection) in rats, Yang et al [135] found an early (4 h) infiltration of T-lymphocytes (CD43+) into the CP. This was blocked by fingolimod (FTY720; a sphingosine-1-phosphate receptor modulator) treatment which also markedly reduced the brain injury in lipopolysaccharide-enhanced hypoxia/ischemia injury.…”

Section: Choroid Plexus As a Responder To Injurymentioning

confidence: 99%

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

Xiang

Routhe

Wilkinson

et al. 2017

Fluids Barriers CNS

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While the impact of hemorrhagic and ischemic strokes on the blood–brain barrier has been extensively studied, the impact of these types of stroke on the choroid plexus, site of the blood-CSF barrier, has received much less attention. The purpose of this review is to examine evidence of choroid plexus injury in clinical and preclinical studies of intraventricular hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage and ischemic stroke. It then discusses evidence that the choroid plexuses are important in the response to brain injury, with potential roles in limiting damage. The overall aim of the review is to highlight deficiencies in our knowledge on the impact of hemorrhagic and ischemic strokes on the choroid plexus, particularly with reference to intraventricular hemorrhage, and to suggest that a greater understanding of the response of the choroid plexus to stroke may open new avenues for brain protection.

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Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

Abstract: Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury

Cited by 70 publications

References 56 publications

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

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