Developmental IL-6 Exposure Favors Production of PDGF-Responsive Multipotential Progenitors at the Expense of Neural Stem Cells and Other Progenitors

Kumari, Ekta; Velloso, Fernando Janczur; Nasuhidehnavi, Azadeh; Somasundaram, Aditya; Savanur, Vibha Harindra; Buono, Krista D.; Levison, Steven W.

doi:10.1016/j.stemcr.2020.03.019

Cited by 15 publications

(18 citation statements)

References 58 publications

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“…This reflects the abnormal cortical structure seen in ASD patients, where there is an increase in the numbers of immature neurons and glial cells in certain areas of the brain [107,116]. Moreover, elevated levels of IL-6 have been shown to increase the proliferation of platelet-derived growth factor (PDGF)-and fibroblast growth factor 2 (FGF-2)-responsive multipotential progenitors (PFMP) in developing mice brain [119]. The PFMPs express IL-6Rα and GP130 receptors required for downstream IL-6 signalling, and it was noted that IL-6 activates pSTAT3 in these cells [119].…”

Section: Interleukin-6mentioning

confidence: 99%

“…Moreover, elevated levels of IL-6 have been shown to increase the proliferation of platelet-derived growth factor (PDGF)-and fibroblast growth factor 2 (FGF-2)-responsive multipotential progenitors (PFMP) in developing mice brain [119]. The PFMPs express IL-6Rα and GP130 receptors required for downstream IL-6 signalling, and it was noted that IL-6 activates pSTAT3 in these cells [119]. right) which consequently produce IL-6 in the maternal compartment of the placenta.…”

Section: Interleukin-6mentioning

confidence: 99%

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Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

Ravaccia

Ghafourian

2020

Biomedicines

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Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterised by impairments in communication, social interaction, and the presence of restrictive and repetitive behaviours. Over the past decade, most of the research in ASD has focused on the contribution of genetics, with the identification of a variety of different genes and mutations. However, the vast heterogeneity in clinical presentations associated with this disorder suggests that environmental factors may be involved, acting as a “second hit” in already genetically susceptible individuals. To this regard, emerging evidence points towards a role for maternal immune system dysfunctions. This literature review considered evidence from epidemiological studies and aimed to discuss the pathological relevance of the maternal immune system in ASD by looking at the proposed mechanisms by which it alters the prenatal environment. In particular, this review focuses on the effects of maternal immune activation (MIA) by looking at foetal brain-reactive antibodies, cytokines and the microbiome. Despite the arguments presented here that strongly implicate MIA in the pathophysiology of ASD, further research is needed to fully understand the precise mechanisms by which they alter brain structure and behaviour. Overall, this review has not only shown the importance of the maternal immune system as a risk factor for ASD, but more importantly, has highlighted new promising pathways to target for the discovery of novel therapeutic interventions for the treatment of such a life-changing disorder.

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Section: Interleukin-6mentioning

confidence: 99%

Section: Interleukin-6mentioning

confidence: 99%

Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

Ravaccia

Ghafourian

2020

Biomedicines

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“…In addition, plateletderived growth factor (PDGF) is crucial for cell survival and proliferation including MSCs and other progenitors. 36 The co-transplantation of MSCs and TCs had better therapeutic effects on ALI development, during which TCs could promote the migration and infiltration of MSCs into the lung. The conditioned medium containing nutrient factors also showed effectiveness in protecting lung against ALI.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of interactions between lung‐origin telocytes and mesenchymal stem cells to treat experimental acute lung injury

Zhang

Song

Shi

et al. 2020

Clinical & Translational Med

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“…We previously showed that transiently increasing systemic levels of IL-6 in neonatal mice affects the balance of stem cells and progenitors within the SVZ and an earlier study had shown that increased circulating levels of IL-6 affects neurogenesis in the hippocampus (Monje et al, 2003;Kumari et al, 2020). Therefore, we postulated that neurogenesis and gliogenesis would be abnormal in IL-6 injected (Rx) mice.…”

Section: Transiently Elevating Circulating Il-6 Reduces Gliogenesis In the Corpus Callosum And Amygdala And Neurogenesis In The Hippocampmentioning

confidence: 99%

“…These progenitors will produce neurons, astrocytes and oligodendrocytes that populate several late developing brain structures that are relevant to the behavioral deficits seen in neurodevelopmental disorders. The SVZ and SGZ rapidly expand during the early 3rd trimester of human development (Monje et al, 2003;Covey et al, 2011;Wei et al, 2011;Storer et al, 2018;Kumari et al, 2020), and in early postnatal development in mice (Semple et al, 2013;Salmaso et al, 2014). While MIA studies conducted to date have manipulated the immune system at mid-gestation, it remains to be established whether elevating IL-6 postnatally in mice is sufficient to alter the trajectory of neural development and elicit behavioral aberrations.…”

Section: Introductionmentioning

confidence: 99%

Perinatal Inflammation Disturbs Secondary Germinal Zone Neurogenesis and Gliogenesis Producing Deficits in Sociability

Velloso

Wadhwa

Kumari

et al. 2021

Preprint

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Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3-6, when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the prefrontal cortex and amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by ∼50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent ∼30% less time socially engaging with sexually receptive females and produced ∼50% fewer ultrasonic vocalizations during mating. They also engaged ∼50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.Significance statementIn these studies, we doubled circulating IL-6 levels in mice from postnatal days 3-6 to test the hypothesis that this would be sufficient to disturb neural development. More specifically, we hypothesized that IL-6 would affect postnatal neural stem cell and progenitor expansion and specification. We show that this transient increase in IL-6 decreases the numbers of granule neurons in the dorsal hippocampus, astrocytes in the prefrontal cortex and amygdala and oligodendrocytes in the corpus callosum. Importantly, this transient increase in IL-6 changes the sociability, communication and repetitive behaviors of the treated mice as adults, which are core symptoms pertinent to several neurodevelopmental psychiatric disorders.

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Developmental IL-6 Exposure Favors Production of PDGF-Responsive Multipotential Progenitors at the Expense of Neural Stem Cells and Other Progenitors

Cited by 15 publications

References 58 publications

Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

Mechanisms of interactions between lung‐origin telocytes and mesenchymal stem cells to treat experimental acute lung injury

Perinatal Inflammation Disturbs Secondary Germinal Zone Neurogenesis and Gliogenesis Producing Deficits in Sociability

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