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Splenic Immune Cells in Experimental Neonatal Hypoxia–Ischemia

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Abstract

Neuroimmune processes contribute to hypoxic–ischemic damage in the immature brain and may play a role in the progression of particular variants of neonatal encephalopathy. The present study was designed to elucidate molecular mediators of interactions between astrocytes, neurons, and infiltrating peripheral immune cells after experimental neonatal hypoxia–ischemia (HI). Splenectomy was performed on postnatal day 7 Sprague–Dawley rats 3 days prior to HI surgery, in which the right common carotid artery was permanently ligated followed by 2 h of hypoxia (8 % O2). Quantitative analysis showed that natural killer (NK) and T cell expression was reduced in spleen but increased in the brain following HI. Elevations in cyclooxygenase-2 (COX-2) expression after HI by immune cells promoted interleukin-15 (IL-15) expression in astrocytes and infiltration of inflammatory cells to site of injury; additionally, these downregulated the prosurvival protein, phosphoinositide-3-kinase (PI3K), resulting in caspase 3-mediated neuronal death. The removal of the largest pool of peripheral immune cells in the body by splenectomy and COX-2 inhibitors as well as rendering NK cells inactive by CD161 knockdown significantly ameliorated cerebral infarct volume at 72 h, diminished body weight loss and brain and systemic organ atrophy, and reduced neurobehavioral deficits at 3 weeks. Herein, we demonstrate with the use of surgical approach (splenectomy) and with pharmacological loss–gain function approach using COX-2 inhibitors/agonists as well as with NK cell-type-specific siRNA that after neonatal HI, the infiltrating peripheral immune cells may modulate downstream targets of cell death and neuroinflammation by COX-2-regulated signals.

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Acknowledgments

The authors thank W. Tong and K. Cordero for their technical assistance on this project. This work was supported by a grant from the National Institutes of Health [NS054685 to J.H.Z.].

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Authors and Affiliations

  1. Department of Human Anatomy and Pathology, Loma Linda University, Loma Linda, CA, USA

    Nancy Fathali

  2. Department of Physiology, Loma Linda University, Loma Linda, CA, USA

    Robert P. Ostrowski, Yu Hasegawa, Tim Lekic, Jiping Tang & John H. Zhang

  3. Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA

    John H. Zhang

  4. Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA

    John H. Zhang

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  1. Nancy Fathali
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  2. Robert P. Ostrowski
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  3. Yu Hasegawa
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  4. Tim Lekic
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  5. Jiping Tang
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  6. John H. Zhang
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Correspondence to John H. Zhang.

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Fathali, N., Ostrowski, R.P., Hasegawa, Y. et al. Splenic Immune Cells in Experimental Neonatal Hypoxia–Ischemia. Transl. Stroke Res. 4, 208–219 (2013). https://doi.org/10.1007/s12975-012-0239-9

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  • DOI: https://doi.org/10.1007/s12975-012-0239-9

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