Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity
The increased incidence of opioid use during pregnancy warrants investigation to reveal the impact of opioid exposure on the developing fetus. Exposure during critical periods of development could have enduring consequences for affected individuals. Particularly, evidence is mounting that developmen...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fped.2020.00272/full |
| _version_ | 1818037264793468928 |
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| author | Jessie Newville Jessie R. Maxwell Jessie R. Maxwell Yuma Kitase Shenandoah Robinson Shenandoah Robinson Lauren L. Jantzie Lauren L. Jantzie Lauren L. Jantzie Lauren L. Jantzie |
| author_facet | Jessie Newville Jessie R. Maxwell Jessie R. Maxwell Yuma Kitase Shenandoah Robinson Shenandoah Robinson Lauren L. Jantzie Lauren L. Jantzie Lauren L. Jantzie Lauren L. Jantzie |
| author_sort | Jessie Newville |
| collection | DOAJ |
| description | The increased incidence of opioid use during pregnancy warrants investigation to reveal the impact of opioid exposure on the developing fetus. Exposure during critical periods of development could have enduring consequences for affected individuals. Particularly, evidence is mounting that developmental injury can result in immune priming, whereby subsequent immune activation elicits an exaggerated immune response. This maladaptive hypersensitivity to immune challenge perpetuates dysregulated inflammatory signaling and poor health outcomes. Utilizing an established preclinical rat model of perinatal methadone exposure, we sought to investigate the consequences of developmental opioid exposure on in vitro activation of peripheral blood mononuclear cells (PBMCs). We hypothesize that PBMCs from methadone-exposed rats would exhibit abnormal chemokine and cytokine expression at baseline, with exaggerated chemokine and cytokine production following immune stimulation compared to saline-exposed controls. On postnatal day (P) 7, pup PMBCs were isolated and cultured, pooling three pups per n. Following 3 and 24 h, the supernatant from cultured PMBCs was collected and assessed for inflammatory cytokine and chemokine expression at baseline or lipopolysaccharide (LPS) stimulation using multiplex electrochemiluminescence. Following 3 and 24 h, baseline production of proinflammatory chemokine and cytokine levels were significantly increased in methadone PBMCs (p < 0.0001). Stimulation with LPS for 3 h resulted in increased tumor necrosis factor (TNF-α) and C-X-C motif chemokine ligand 1 (CXCL1) expression by 3.5-fold in PBMCs from methadone-exposed PBMCs compared to PBMCs from saline-exposed controls (p < 0.0001). Peripheral blood mononuclear cell hyperreactivity was still apparent at 24 h of LPS stimulation, evidenced by significantly increased TNF-α, CXCL1, interleukin 6 (IL-6), and IL-10 production by methadone PMBCs compared to saline control PBMCs (p < 0.0001). Together, we provide evidence of increased production of proinflammatory molecules from methadone PBMCs at baseline, in addition to sustained hyperreactivity relative to saline-exposed controls. Exaggerated peripheral immune responses exacerbate inflammatory signaling, with subsequent consequences on many organ systems throughout the body, such as the developing nervous system. Enhanced understanding of these inflammatory mechanisms will allow for appropriate therapeutic development for infants who were exposed to opioids during development. Furthermore, these data highlight the utility of this in vitro PBMC assay technique for future biomarker development to guide specific treatment for patients exposed to opioids during gestation. |
| first_indexed | 2024-12-10T07:24:05Z |
| format | Article |
| id | doaj.art-95901123f25649d5be87af4b9c941ea1 |
| institution | Directory Open Access Journal |
| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-12-10T07:24:05Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pediatrics |
| spelling | doaj.art-95901123f25649d5be87af4b9c941ea12022-12-22T01:57:44ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602020-06-01810.3389/fped.2020.00272524867Perinatal Opioid Exposure Primes the Peripheral Immune System Toward HyperreactivityJessie Newville0Jessie R. Maxwell1Jessie R. Maxwell2Yuma Kitase3Shenandoah Robinson4Shenandoah Robinson5Lauren L. Jantzie6Lauren L. Jantzie7Lauren L. Jantzie8Lauren L. Jantzie9Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United StatesDepartment of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United StatesDepartments of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, United StatesDivision of Neonatal-Perinatal Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Neonatal-Perinatal Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDivision of Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, Kennedy Krieger Institute, Baltimore, MD, United StatesThe increased incidence of opioid use during pregnancy warrants investigation to reveal the impact of opioid exposure on the developing fetus. Exposure during critical periods of development could have enduring consequences for affected individuals. Particularly, evidence is mounting that developmental injury can result in immune priming, whereby subsequent immune activation elicits an exaggerated immune response. This maladaptive hypersensitivity to immune challenge perpetuates dysregulated inflammatory signaling and poor health outcomes. Utilizing an established preclinical rat model of perinatal methadone exposure, we sought to investigate the consequences of developmental opioid exposure on in vitro activation of peripheral blood mononuclear cells (PBMCs). We hypothesize that PBMCs from methadone-exposed rats would exhibit abnormal chemokine and cytokine expression at baseline, with exaggerated chemokine and cytokine production following immune stimulation compared to saline-exposed controls. On postnatal day (P) 7, pup PMBCs were isolated and cultured, pooling three pups per n. Following 3 and 24 h, the supernatant from cultured PMBCs was collected and assessed for inflammatory cytokine and chemokine expression at baseline or lipopolysaccharide (LPS) stimulation using multiplex electrochemiluminescence. Following 3 and 24 h, baseline production of proinflammatory chemokine and cytokine levels were significantly increased in methadone PBMCs (p < 0.0001). Stimulation with LPS for 3 h resulted in increased tumor necrosis factor (TNF-α) and C-X-C motif chemokine ligand 1 (CXCL1) expression by 3.5-fold in PBMCs from methadone-exposed PBMCs compared to PBMCs from saline-exposed controls (p < 0.0001). Peripheral blood mononuclear cell hyperreactivity was still apparent at 24 h of LPS stimulation, evidenced by significantly increased TNF-α, CXCL1, interleukin 6 (IL-6), and IL-10 production by methadone PMBCs compared to saline control PBMCs (p < 0.0001). Together, we provide evidence of increased production of proinflammatory molecules from methadone PBMCs at baseline, in addition to sustained hyperreactivity relative to saline-exposed controls. Exaggerated peripheral immune responses exacerbate inflammatory signaling, with subsequent consequences on many organ systems throughout the body, such as the developing nervous system. Enhanced understanding of these inflammatory mechanisms will allow for appropriate therapeutic development for infants who were exposed to opioids during development. Furthermore, these data highlight the utility of this in vitro PBMC assay technique for future biomarker development to guide specific treatment for patients exposed to opioids during gestation.https://www.frontiersin.org/article/10.3389/fped.2020.00272/fullmethadonelymphocytePBMCSPIHRblood mononuclear cellneuroinflammation |
| spellingShingle | Jessie Newville Jessie R. Maxwell Jessie R. Maxwell Yuma Kitase Shenandoah Robinson Shenandoah Robinson Lauren L. Jantzie Lauren L. Jantzie Lauren L. Jantzie Lauren L. Jantzie Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity Frontiers in Pediatrics methadone lymphocyte PBMC SPIHR blood mononuclear cell neuroinflammation |
| title | Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity |
| title_full | Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity |
| title_fullStr | Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity |
| title_full_unstemmed | Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity |
| title_short | Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity |
| title_sort | perinatal opioid exposure primes the peripheral immune system toward hyperreactivity |
| topic | methadone lymphocyte PBMC SPIHR blood mononuclear cell neuroinflammation |
| url | https://www.frontiersin.org/article/10.3389/fped.2020.00272/full |
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