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Leavenworth, Jianmei

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Leavenworth

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Jianmei

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Leavenworth, Jianmei
Author's Publications: search.filters.isAuthorOfPublication.1b094908-4476-4483-867a-0c0ab4911b98

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    The effect of osteopontin and osteopontin-derived peptides on preterm brain injury
    (BioMed Central, 2014) Albertsson, Anna-Maj; Zhang, Xiaoli; Leavenworth, Jianmei; Bi, Dan; Nair, Syam; Qiao, Lili; Hagberg, Henrik; Mallard, Carina; Cantor, Harvey; Wang, Xiaoyang
    Background: Osteopontin (OPN) is a highly phosphorylated sialoprotein and a soluble cytokine that is widely expressed in a variety of tissues, including the brain. OPN and OPN-derived peptides have been suggested to have potential neuroprotective effects against ischemic brain injury, but their role in preterm brain injury is unknown. Methods: We used a hypoxia-ischemia (HI)-induced preterm brain injury model in postnatal day 5 mice. OPN and OPN-derived peptides were given intracerebroventricularly and intranasally before HI. Brain injury was evaluated at 7 days after the insults. Results: There was a significant increase in endogenous OPN mRNA and OPN protein in the mouse brain after the induction of HI at postnatal day 5. Administration of full-length OPN protein and thrombin-cleaved OPN did not affect preterm brain injury. This was demonstrated with both intracerebroventricular and intranasal administration of OPN as well as in OPN-deficient mice. Interestingly, both N134–153 and C154–198 OPN-derived peptides increased the severity of brain injury in this HI-induced preterm brain injury model. Conclusions: The neuroprotective effects of OPN are age-dependent, and, in contrast to the more mature brain, OPN-derived peptides potentiate injury in postnatal day 5 mice. Intranasal administration is an efficient way of delivering drugs to the central nervous system (CNS) in neonatal mice and is likely to be an easy and noninvasive method of drug delivery to the CNS in preterm infants.
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    The immune response after hypoxia-ischemia in a mouse model of preterm brain injury
    (BioMed Central, 2014) Albertsson, Anna-Maj; Bi, Dan; Duan, Luqi; Zhang, Xiaoli; Leavenworth, Jianmei; Qiao, Lili; Zhu, Changlian; Cardell, Susanna; Cantor, Harvey; Hagberg, Henrik; Mallard, Carina; Wang, Xiaoyang
    Background: Preterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury. Methods: C57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining. Results: HI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model. Conclusions: We have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury.
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    A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
    (2014) Leavenworth, Jianmei; Verbinnen, Bert; Yin, Jie; Huang, Huicong; Cantor, Harvey
    Follicular helper T (TFH) cells and follicular regulatory T (TFR) cells regulate the quantity and quality of humoral immunity. Although both cell types highly express the co-stimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that ICOS activation in CD4+ T cells promotes the interaction of the p85α regulatory subunit of the signaling kinase PI3K and intracellular osteopontin (OPN-i), followed by nuclear translocation of OPN-i, interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 expression by OPN-i is essential for sustained TFH and TFR cell responses and regulation of the germinal center B cell response to antigen. As such, the p85α–OPN-i axis represents a molecular bridge that couples ICOS activation to Bcl-6-dependent functional differentiation of TFH and TFR cells and suggests new therapeutic avenues to manipulate their responses.