Maternal inflammation and its ramifications on fetal neurodevelopment
2022; Elsevier BV; Volume: 43; Issue: 3 Linguagem: Inglês
10.1016/j.it.2022.01.007
ISSN1471-4981
AutoresHo‐Keun Kwon, Gloria B. Choi, Jun R. Huh,
Tópico(s)Adolescent and Pediatric Healthcare
ResumoAn increased risk of neurodevelopmental and psychiatric disorders in children has been associated with their exposure to heightened inflammation in the womb caused by respiratory infections or other inflammatory stimuli.Rodent models have provided a wealth of information on how maternal immune activation (MIA) influences brain development and animal behaviors.Maternal gut bacteria shape maternal immune function and influence the development of autism-like phenotypes in offspring.A comprehensive understanding of the gut bacteria-immune-neuro interaction in MIA is crucial to developing diagnostic and preventive measures for high-risk pregnant women and identifying targets for treating inflammation-induced neurodevelopmental disorders. Exposure to heightened inflammation in pregnancy caused by infections or other inflammatory insults has been associated with the onset of neurodevelopmental and psychiatric disorders in children. Rodent models have provided unique insights into how this maternal immune activation (MIA) disrupts brain development. Here, we discuss the key immune factors involved, highlight recent advances in determining the molecular and cellular pathways of MIA, and review how the maternal immune system affects fetal development. We also examine the roles of microbiomes in shaping maternal immune function and the development of autism-like phenotypes. A comprehensive understanding of the gut bacteria-immune-neuro interaction in MIA is essential for developing diagnostic and therapeutic measures for high-risk pregnant women and identifying targets for treating inflammation-induced neurodevelopmental disorders. Exposure to heightened inflammation in pregnancy caused by infections or other inflammatory insults has been associated with the onset of neurodevelopmental and psychiatric disorders in children. Rodent models have provided unique insights into how this maternal immune activation (MIA) disrupts brain development. Here, we discuss the key immune factors involved, highlight recent advances in determining the molecular and cellular pathways of MIA, and review how the maternal immune system affects fetal development. We also examine the roles of microbiomes in shaping maternal immune function and the development of autism-like phenotypes. A comprehensive understanding of the gut bacteria-immune-neuro interaction in MIA is essential for developing diagnostic and therapeutic measures for high-risk pregnant women and identifying targets for treating inflammation-induced neurodevelopmental disorders. A developing fetus absorbs nutrients and other key resources from maternal circulation while avoiding potentially harmful effectors, including those produced from the maternal immune system that might view the fetus as foreign [1.Erlebacher A. 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This review summarizes recent findings of how MIA affects brain development and can promote neurodevelopmental illness in the offspring (Figure 1). Postnatal exposure to inflammation also induces long-term consequences in animal health and has been recently reviewed [6.Bangma J.T. et al.Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm.Pediatr. Res. 2021; 89: 326-335Crossref PubMed Google Scholar]. Here, we focus on the ramifications of prenatal exposure to MIA. In addition to genetic components, environmental factors likely contribute to the onset of neuropsychiatric and neurodevelopmental disorders, such as bipolar disorder, schizophrenia, and ASD. Epidemiological data indicate a strong association between increased infection rates and neurodevelopmental disorders. For example, the 1918–1919 influenza virus pandemic was suggested to increase the risk of schizophrenia [7.Kendell R.E. Kemp I.W. 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Disord. 2010; 40: 1423-1430Crossref PubMed Scopus (529) Google Scholar] also supports the same notion: infection or inflammation requiring hospitalization of pregnant women was associated with the risk of developing psychiatric disorders in their children. Therefore, pathogen-induced MIA, and not specific pathogens, has been deemed a pivotal factor in driving persistent changes in brain development and behaviors in offspring. In line with this idea, various inflammatory conditions during pregnancy are shown to enhance the risk of neurodevelopmental disorders. For instance, maternal autoimmune disorders, allergies, and asthma have been reported as risk factors for developing ASD and schizophrenia in humans [16.Croen L.A. et al.Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study.Arch. Pediatr. Adolesc. 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Epidemiol. 2013; 178: 209-220Crossref PubMed Scopus (75) Google Scholar] that directly or indirectly elevate immune responses, have also been linked to an increased risk of ASD [2.Arck P.C. Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health.Nat. Med. 2013; 19: 548-556Crossref PubMed Scopus (353) Google Scholar,5.Knuesel I. et al.Maternal immune activation and abnormal brain development across CNS disorders.Nat. Rev. Neurol. 2014; 10: 643-660Crossref PubMed Scopus (425) Google Scholar]. Mechanistically, a series of recent human studies have shown that pregnant mothers exposed to MIA can have dysregulated cytokine production, such as for interleukins 6 (IL-6) and 17a (IL-17a), which are associated with cognitive impairment and the risk of developing ASD in their children [3.Rudolph M.D. et al.Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring.Nat. 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Although further studies are needed to clarify which key inflammatory markers or pathways are triggered by different pathogenic infections and which genetic or environmental factors elicit or contribute to the development of certain brain disorders, the available evidence suggests that MIA can act as a prenatal ‘primer’ that can instigate a range of neurodevelopmental and neuropsychiatric disorders in offspring. Presently, rapid globalization, exploding population growth, emerging novel infectious agents, and a resurgence of classical contagious diseases (including measles, mumps, and polio) may be laying the groundwork for increased rates of opportunistic infections in pregnant women. Combined with the rising rates of inflammatory conditions, which may include autoimmune disorders, allergies, and asthma, these factors might account for or contribute to recent increases in neurodevelopmental disorders in the global pediatric population [24.Boyle C.A. et al.Trends in the prevalence of developmental disabilities in US children, 1997-2008.Pediatrics. 2011; 127: 1034-1042Crossref PubMed Scopus (1071) Google Scholar]. The current coronavirus disease 2019 (COVID-19) pandemic has already affected more than 2.5 billion individuals (at the time this article was written), including pregnant women. These alarming cases make it imperative to understand how MIA affects inflammatory responses in pregnant women and can contribute to promoting neurodevelopmental disorders in affected children. Indeed, data already indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, like some other respiratory infections, can elicit pregnancy complications, including fetal growth restriction, fetal distress, and preterm birth [25.Dashraath P. et al.Coronavirus disease 2019 (COVID-19) pandemic and pregnancy.Am. J. Obstet. Gynecol. 2020; 222: 521-531Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar]. We describe various ways of inducing MIA, maternal immune pathways eliciting neurodevelopmental pathologies, and the role of gut bacteria in contributing to MIA-induced pathologies. We also highlight key unanswered questions and future directions. Animal models have facilitated studies of complex human brain diseases. Earlier rodent models of MIA were established with an initial focus on schizophrenia [26.Zuckerman L. Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring.J. Psychiatr. 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These and other studies extensively characterized behavioral abnormalities in MIA-affected offspring, particularly those reminiscent of human ASD and schizophrenia patients, including alteration and deficits in pre-pulse inhibition, cognition, sociability, repetitive behavior, and increased sensitivity to antipsychotic drugs compared with controls [13.Patterson P.H. Immune involvement in schizophrenia and autism: etiology, pathology and animal models.Behav. Brain Res. 2009; 204: 313-321Crossref PubMed Scopus (524) Google Scholar]. Importantly, these MIA-induced behavioral abnormalities have been similarly reproduced in non-human primate (NHP) models [30.Careaga M. et al.Maternal immune activation and autism spectrum disorder: from rodents to nonhuman and human primates.Biol. 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Risk factors include (but are not limited to) pesticides, air pollutants (fine particles, diesel, NO2, and heavy metals), and phthalates [32.Chang Y.-C. et al.Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice.Part. Fibre Toxicol. 2018; 15: 18Crossref PubMed Google Scholar,52.Messerlian C. et al.Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior.Environ. Res. 2017; 158: 720-728Crossref PubMed Google Scholar]. A recent study with more than 1700 children born from 1990 to 2002 in the US revealed a strong association, specifically in the third trimester, between maternal exposure to fine particles, or particulate matter 2.5 (PM2.5), and increased ASD prevalence [19.Raz R. et al.Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case-control analysis within the Nurses' Health Study II Cohort.Environ. 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Therefore, further investigations are needed to conclusively assess a causal relationship between various environmental risk factors, MIA, and its long-term pediatric consequences. In humans, studies have shown a strong association between excessive maternal stress, such as traumatic experiences, anxiety, and depression, with prenatal inflammation, impaired brain development, and psychiatric disorders in offspring [58.Walder D.J. et al.Prenatal maternal stress predicts autism traits in 6½ year-old children: project ice storm.Psychiatry Res. 2014; 219: 353-360Crossref PubMed Google Scholar,59.Kinney D.K. et al.Autism prevalence following prenatal exposure to hurricanes and tropical storms in Louisiana.J. Autism Dev. Disord. 2008; 38: 481-488Crossref PubMed Scopus (133) Google Scholar]. 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