640 - Cytokine and iron markers from brain-derived exosomes indicate activation of anti-inflammatory mechanisms in infants born to obese mothers
Monday, April 28, 2025
7:00am – 9:15am HST
Publication Number: 640.4535
Zia Maxim, University of Minnesota Medical School, Minneapolis, MN, United States; Narmin Javadova, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Sowmya Kruttiventi, University of South Dakota, Sanford School of Medicine, Sioux Falls, SD, United States; Manjula Munirathinam, University of Minnesota Medical School, Minneapolis, MN, United States; Pamela Kling, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Michelle Baack, University of South Dakota, Sanford School of Medicine, Sioux Falls, SD, United States; Phu V. Tran, University of Minnesota Medical School, Minneapolis, MN, United States; Michael K. Georgieff, University of Minnesota, St. Paul, MN, United States
Research Scientist 2 University of Minnesota Medical School Minneapolis, Minnesota, United States
Background: Non-infectious neuroinflammation (NI) has been linked to neurodevelopmental disorders (ASD, ADHD). Assessment of NI relies on cerebrospinal fluid (CSF) evaluation, which is unrealistic for asymptomatic infants. Similarly, plasma inflammation biomarkers may not accurately reflect presence or absence of inflammation specifically within the brain. Thus, it is necessary to establish unambiguous and reliable brain-specific biomarkers from plasma that directly index NI. Objective: Establish a panel of brain-derived biomarkers (cytokines, chemokines) measurable in plasma as metrics of NI Design/Methods: Brain-derived exosomes (BDEs) from banked cord blood plasma from healthy, uninfected, term newborns, gestational age ≥36 weeks, born by scheduled, uncomplicated cesarean delivery at a single center (Sanford Health, SD; IRB STUDY0000051). Exosomes were isolated from plasma (100μl) using the Exo-Spin 96 kit. BDEs were enriched by immunoprecipitation using antibodies targeting contactin-2 (CNTN2), a brain-specific cell surface protein (1 μg, Invitrogen) and validated using a nanoparticle tracker and dot blot assessing exosome markers (CD9, CD63, CD81). Concentrations of neuronal chemokine (CX3CL1), pro-inflammatory cytokines (CRP, TNFa), nerve growth factor (BDNF), cell metabolism marker (PARK7), astrocyte function marker (S100B), and iron indices (Ferritin, transferrin receptor [TfR]) carried by BDEs (2.0E+9 particles) were quantified using state-of-the-art Luminex assays. Data were analyzed using t-test with alpha < 0.05. Results: Demographics are shown (Table). Compared to newborns of non-obese mothers (N=29), BDEs from newborns of obese mothers (N=51) showed higher levels of CX3CL1 (p < 0.05), PARK7 (p < 0.01), BDNF (p < 0.001), and ferritin (p < 0.001), but lower levels of TNFa (p < 0.001), CRP (p < 0.001), S100B (p < 0.001), and TfR (p < 0.001).
Conclusion(s): Given the anti-inflammatory role of CX3CL1/CX3CR1 signaling in microglia, the findings indicate increased brain anti-inflammatory response, cellular metabolism, and neuroprotection/plasticity accompanied by increased neural functional iron deficiency in the offspring of obese mothers (figure). The discovery of quantifiable BDE biomarkers for NI and brain iron status will be significant in identifying infants at risk for long-term adverse health outcomes before they become apparent later in life.
