PMID- 30465871 OWN - NLM STAT- MEDLINE DCOM- 20200421 LR - 20210109 IS - 1873-474X (Electronic) IS - 0736-5748 (Print) IS - 0736-5748 (Linking) VI - 77 DP - 2019 Oct TI - Placental Macrophages: A Window Into Fetal Microglial Function in Maternal Obesity. PG - 60-68 LID - 10.1016/j.ijdevneu.2018.11.004 [doi] AB - Fetal placental macrophages and microglia (resident brain macrophages) have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual's lifetime. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living fetus or neonate is impossible. We sought to test the hypothesis that maternal obesity would prime both placental macrophages and fetal brain microglia to overrespond to an immune challenge, thus providing a window into microglial function using placental cells. Obesity was induced in C57BL/6 J mice using a 60% high-fat diet. On embryonic day 17.5, fetal brain microglia and corresponding CD11b + placental cells were isolated from fresh tissue. Cells were treated with media or lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-alpha) production by stimulated and unstimulated cells was quantified via ELISA. We demonstrate for the first time that the proinflammatory cytokine production of CD11b + placental cells is strongly correlated with that of brain microglia (Spearman's rho = 0.73, p = 0.002) in the setting of maternal obesity. Maternal obesity-exposed CD11b + cells had an exaggerated response to LPS compared to controls, with a 5.1-fold increase in TNF-alpha production in placentas (p = 0.003) and 3.8-fold increase in TNF-alpha production in brains (p = 0.002). In sex-stratified analyses, only male obesity-exposed brains and placentas had significant increase in TNF-alpha production in response to LPS. Taken together, these data suggest that maternal obesity primes both placental macrophages and fetal brain microglia to overproduce a proinflammatory cytokine in response to immune challenge. Male brain and placental immune response is more marked than female in this setting. Given that fetal microglial priming may impact neuroimmune function throughout the lifespan, these data could provide insight into the male predominance of certain neurodevelopmental morbidities linked to maternal obesity, including cognitive dysfunction, autism spectrum disorder, and ADHD. Placental CD11b+ macrophages may have the potential to serve as an accessible biomarker of aberrant fetal brain immune activation in maternal obesity. This finding may have broader implications for assaying the impact of other maternal exposures on fetal brain development. CI - Copyright (c) 2018 ISDN. Published by Elsevier Ltd. All rights reserved. FAU - Edlow, Andrea G AU - Edlow AG AD - Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Massachusetts General Hospital, Vincent Center for Reproductive Biology. FAU - Glass, Ruthy M AU - Glass RM AD - Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Massachusetts General Hospital, Vincent Center for Reproductive Biology. FAU - Smith, Caroline J AU - Smith CJ AD - Pediatrics and Program in Neuroscience, Harvard Medical School, Lurie Center for Autism, MassGeneral Hospital for Children. FAU - Tran, Phuong Kim AU - Tran PK AD - Pediatrics and Program in Neuroscience, Harvard Medical School, Lurie Center for Autism, MassGeneral Hospital for Children. FAU - James, Kaitlyn AU - James K AD - Massachusetts General Hospital, Deborah Kelly Center for Outcomes Research. FAU - Bilbo, Staci AU - Bilbo S AD - Pediatrics and Program in Neuroscience, Harvard Medical School, Lurie Center for Autism, MassGeneral Hospital for Children. LA - eng GR - K12 HD000849/HD/NICHD NIH HHS/United States GR - R01 ES025549/ES/NIEHS NIH HHS/United States PT - Journal Article DEP - 20181120 PL - United States TA - Int J Dev Neurosci JT - International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience JID - 8401784 RN - 0 (Lipopolysaccharides) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Diet, High-Fat MH - Female MH - Lipopolysaccharides/pharmacology MH - Macrophages/drug effects/*metabolism MH - Male MH - Mice MH - Microglia/drug effects/*metabolism MH - Obesity, Maternal/*metabolism MH - Placenta/drug effects/*metabolism MH - Pregnancy MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC6527487 MID - NIHMS1514357 OTO - NOTNLM OT - Hofbauer cells OT - fetal brain OT - inflammation OT - maternal obesity OT - microglia OT - placenta EDAT- 2018/11/23 06:00 MHDA- 2020/04/22 06:00 PMCR- 2020/10/01 CRDT- 2018/11/23 06:00 PHST- 2018/08/30 00:00 [received] PHST- 2018/11/05 00:00 [revised] PHST- 2018/11/14 00:00 [accepted] PHST- 2018/11/23 06:00 [pubmed] PHST- 2020/04/22 06:00 [medline] PHST- 2018/11/23 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - 10.1016/j.ijdevneu.2018.11.004 [doi] PST - ppublish SO - Int J Dev Neurosci. 2019 Oct;77:60-68. doi: 10.1016/j.ijdevneu.2018.11.004. Epub 2018 Nov 20.