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Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis.
Exp Neurol. 2018 03; 301(Pt B):110-119.EN

Abstract

In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and childhood disability. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. While studies show CHORIO contributes to preterm CNS injury and is also a common independent risk factor for brain injury in term infants, the molecular mechanisms mediating inflammation in the placental-fetal-brain axis that result in PBI remain a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been clinically implicated in CHORIO and in mature CNS injury, although their specific role in PBI pathophysiology is poorly defined. Given CXCL1/CXCR2 signaling is essential to neural cell development and neutrophil recruitment, a key pathological hallmark of CHORIO, we hypothesized CHORIO would upregulate CXCL1/CXCR2 expression in the placenta and fetal circulation, concomitant with increased CXCL1/CXCR2 signaling in the developing brain, immune cell activation, neutrophilia, and microstructural PBI. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague Dawley rats to induce CHORIO. Specifically, uterine arteries were occluded for 60min to induce placental transient systemic hypoxia-ischemia (TSHI), followed by intra-amniotic injection of lipopolysaccharide (LPS). Pups were born at E22. Placentae, serum and brain were collected along an extended time course from E19 to postnatal day (P)15 and analyzed using multiplex electrochemiluminescence (MECI), Western blot, qPCR, flow cytometry (FC) and diffusion tensor imaging (DTI). Results demonstrate that compared to sham, CHORIO increases placental CXCL1 and CXCR2 mRNA levels, concomitant with increased CXCR2+ neutrophils. Interestingly, pup serum CXCL1 expression in CHORIO parallels this increase, with sustained elevation through P15. Analyses of CHORIO brains reveal similarly increased CXCL1/CXCR2 expression through P7, together with increased neutrophilia, microgliosis and peripheral macrophages. Similar to the placenta, cerebral neutrophilia was defined by increased CXCR2 surface expression and elevated myeloperoxidase expression (MPO), consistent with immune cell activation. Evaluation of microstructural brain injury at P15 with DTI reveals aberrant microstructural integrity in the callosal and capsular white matter, with reduced fractional anisotropy in superficial and deep layers of overlying cortex. In summary, using an established model of CHORIO that exhibits mature CNS deficits mimicking those of preterm survivors, we show CHORIO induces injury throughout the placental-fetal-brain axis with a CXCL1/CXCR2 inflammatory signature, neutrophilia, and microstructural abnormalities. These data are concomitant with abnormal cerebral CXCL1/CXCR2 expression, and support temporal aberrations in CXCL1/CXCR2 and neutrophil dynamics in the placental-fetal-brain axis following CHORIO. These investigations define novel targets for directed therapies for infants at high risk for PBI.

Authors+Show Affiliations

Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, United States.Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United States.Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, United States.Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, United States.Division of Pediatric Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, United States.Division of Pediatric Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, United States.Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United States.Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, United States; Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United States. Electronic address: LJantzie@salud.unm.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29117499

Citation

Yellowhair, Tracylyn R., et al. "Preclinical Chorioamnionitis Dysregulates CXCL1/CXCR2 Signaling Throughout the Placental-fetal-brain Axis." Experimental Neurology, vol. 301, no. Pt B, 2018, pp. 110-119.
Yellowhair TR, Noor S, Maxwell JR, et al. Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis. Exp Neurol. 2018;301(Pt B):110-119.
Yellowhair, T. R., Noor, S., Maxwell, J. R., Anstine, C. V., Oppong, A. Y., Robinson, S., Milligan, E. D., & Jantzie, L. L. (2018). Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis. Experimental Neurology, 301(Pt B), 110-119. https://doi.org/10.1016/j.expneurol.2017.11.002
Yellowhair TR, et al. Preclinical Chorioamnionitis Dysregulates CXCL1/CXCR2 Signaling Throughout the Placental-fetal-brain Axis. Exp Neurol. 2018;301(Pt B):110-119. PubMed PMID: 29117499.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis. AU - Yellowhair,Tracylyn R, AU - Noor,Shahani, AU - Maxwell,Jessie R, AU - Anstine,Christopher V, AU - Oppong,Akosua Y, AU - Robinson,Shenandoah, AU - Milligan,Erin D, AU - Jantzie,Lauren L, Y1 - 2017/11/05/ PY - 2017/06/16/received PY - 2017/10/28/revised PY - 2017/11/03/accepted PY - 2017/11/9/pubmed PY - 2018/11/7/medline PY - 2017/11/9/entrez KW - Chemokine KW - Encephalopathy of prematurity KW - Microglia KW - Neuroinflammation KW - Neutrophil KW - Perinatal brain injury SP - 110 EP - 119 JF - Experimental neurology JO - Exp. Neurol. VL - 301 IS - Pt B N2 - In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and childhood disability. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. While studies show CHORIO contributes to preterm CNS injury and is also a common independent risk factor for brain injury in term infants, the molecular mechanisms mediating inflammation in the placental-fetal-brain axis that result in PBI remain a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been clinically implicated in CHORIO and in mature CNS injury, although their specific role in PBI pathophysiology is poorly defined. Given CXCL1/CXCR2 signaling is essential to neural cell development and neutrophil recruitment, a key pathological hallmark of CHORIO, we hypothesized CHORIO would upregulate CXCL1/CXCR2 expression in the placenta and fetal circulation, concomitant with increased CXCL1/CXCR2 signaling in the developing brain, immune cell activation, neutrophilia, and microstructural PBI. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague Dawley rats to induce CHORIO. Specifically, uterine arteries were occluded for 60min to induce placental transient systemic hypoxia-ischemia (TSHI), followed by intra-amniotic injection of lipopolysaccharide (LPS). Pups were born at E22. Placentae, serum and brain were collected along an extended time course from E19 to postnatal day (P)15 and analyzed using multiplex electrochemiluminescence (MECI), Western blot, qPCR, flow cytometry (FC) and diffusion tensor imaging (DTI). Results demonstrate that compared to sham, CHORIO increases placental CXCL1 and CXCR2 mRNA levels, concomitant with increased CXCR2+ neutrophils. Interestingly, pup serum CXCL1 expression in CHORIO parallels this increase, with sustained elevation through P15. Analyses of CHORIO brains reveal similarly increased CXCL1/CXCR2 expression through P7, together with increased neutrophilia, microgliosis and peripheral macrophages. Similar to the placenta, cerebral neutrophilia was defined by increased CXCR2 surface expression and elevated myeloperoxidase expression (MPO), consistent with immune cell activation. Evaluation of microstructural brain injury at P15 with DTI reveals aberrant microstructural integrity in the callosal and capsular white matter, with reduced fractional anisotropy in superficial and deep layers of overlying cortex. In summary, using an established model of CHORIO that exhibits mature CNS deficits mimicking those of preterm survivors, we show CHORIO induces injury throughout the placental-fetal-brain axis with a CXCL1/CXCR2 inflammatory signature, neutrophilia, and microstructural abnormalities. These data are concomitant with abnormal cerebral CXCL1/CXCR2 expression, and support temporal aberrations in CXCL1/CXCR2 and neutrophil dynamics in the placental-fetal-brain axis following CHORIO. These investigations define novel targets for directed therapies for infants at high risk for PBI. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/29117499/Preclinical_chorioamnionitis_dysregulates_CXCL1/CXCR2_signaling_throughout_the_placental_fetal_brain_axis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(17)30293-5 DB - PRIME DP - Unbound Medicine ER -