Human studies supporting a role of cytokines in neurodevelopment

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The essential role of cytokines during embryonic development

Cytokines can have pro- or anti-inflammatory functions and be neuroprotective or destructive, depending on their timing of expression (age-related), level of expression (acute vs. chronic) and concentrations (Morganti-Kossman 1997). During neurogenesis, radial glial cells (RGCs) derived from neuroepithelial cells (Hatakeyama et al. 2004) act as precursors for all neurons, astrocytes, oligodendrocytes and adult neural stem cells and guide the migration of immature neurons to their final location (Pinto and Götz 2007). The cytokines of particular importance during this process are the gp130/IL-6 family cytokines and the bone morphogenetic proteins (BMPs), part of the TGFβ superfamily. Members of the gp130 family cytokines, such as IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) regulate RGCs self-renewal (Gregg and Weiss 2005; Hatta et al. 2002; Yoshimatsu et al. 2006), while inhibition of the neural induction repressors BMPs contribute to neural induction (Gaulden and Reiter 2008). Moreover, chemokines, such as the CXCL12 through their receptor CXCR4, promote migration and proliferation of newly generated neurons and glia (Klein et al. 2001; Zhu et al. 2002; Lu, Grove, and Miller 2002), and play an important role in axonal pathfinding (Chalasani et al. 2003). Another important role of cytokines during neurodevelopment is that of regulators of synaptogenesis and synaptic pruning (Sedel et al. 2004; Barker et al. 2001), such as in the case of microglia-derived TNF.

Microglia: neuroimmune interactions in shaping neuronal circuitry

Apart from cytokines, immune cells, and in particular, microglia, also have specific roles in neurodevelopment during the early stages of neurogenesis, as well as during the postnatal period and adulthood. They are the first glial cells to migrate into the CNS during embryonic brain development. This is an important period of neuronal migration, during which microglia guide neurons and their axons to form prenatal circuits (Colonna and Butovsky 2017), as well as influence neural precursor cell differentiation (Aarum et al. 2003). Moreover, in vitro coculture of microglial and neuronal stem cells (NSCs) show that microglial-secreted factors are necessary for NSC self-renewal (Walton et al. 2006). During postnatal development, microglia modulate synaptic pruning. This activity is achieved by the phagocytosis of dendritic spines that did not receive synaptic inputs (Colonna and Butovsky 2017). Also, microglia phagocyte the debris of surnumerary neurons which had to be eliminated as they were unable to form functional circuits. All these effects contribute to microglial shaping of the neuronal networks during early development.

Neonatal immune system vs. adult immune system

There is increasing knowledge about the involvement of immune cells and their mediators in early brain development, as well as the immunological differences between the perinatal and adult brain (Garay and McAllister 2010). In comparison to the adult immune system, the neonatal immune system is polarized towards Th2 responses (Maródi 2002; Levy 2007; Wynn and Levy 2010). Moreover, stimulated neonatal serum monocytes secrete less TNFα, a Th1-polarising cytokine, and more IL-6, a Th2-polarising cytokine, than adult monocytes (Angelone et al. 2006). There are also clear age-related differences in immune responses in the brain. In the adult CNS and in particular in the brain parenchyma, the response to inflammatory stimuli, such as pro-inflammatory cytokines or LPS, is characterized by the ability to restrict peripheral leukocyte migration (Andersson, Perry and Gordon, 1992a; Andersson, Perry and Gordon, 1992b). In contrast, during the early stages of mouse CNS development, neutrophil and monocyte are recruited to the brain parenchyma upon endotoxin injection, but the characteristics of this response are age-dependent (Lawson and Perry 1995): immediately after birth, at post-natal day (P) 0, the brain inflammatory response is relatively weak, showing reduced microglial response upon intracerebral LPS administration, as well as slow and reduced neutrophil and monocyte recruitment from the periphery. By P7, the microglial response following LPS injection becomes fast and efficient and there is increased neutrophil recruitment, as compared to P0 (Lawson and Perry 1995).

The essential role of cytokines during postnatal development

During postnatal development, cytokines in homeostatic conditions have been shown to display a dynamic pattern of expression, both in blood and brain tissue. This pattern is age- and region-specific, which is suggestive of the need for a timely and restricted expression of specific cytokines during neurodevelopment (Garay et al. 2013; Deverman and Patterson 2009; Dziegielewska et al. 2000; Bauer, Kerr, and Patterson 2007). The expression of IL-6, a cytokine involved in neurogenesis, as well as its receptor, IL-6R, have been demonstrated to be tissue-specific in the rat brain, depending on the postnatal developmental stage: Il6 and Il6r mRNAs levels are highest in adult hippocampus, whereas the levels of Il6 mRNA are highest in all other brain regions during early brain development (Gadient and Otten 1994).

Specific role of cytokines in neurodevelopment: the example of TNF

Tumour Necrosis Factor (TNF) is a proinflammatory cytokine historically known as a chief orchestrator of the innate immune response (Holbrook et al. 2019). TNF is normally present in minute amounts, however, following an immune challenge, TNF is massively induced in activated macrophages in peripheral tissues. TNF is expressed as a 27 kDa transmembrane form (mTNF) which acts by cell-to-cell contacts, and as a soluble 17 kDa form (sTNF) produced by regulated cleavage of mTNF that is released in tissues and blood (Kriegler et al. 1988). TNF signals through two membrane receptors, TNFR1 and TNFR2. While both sTNF and mTNF activate TNFR1 signalling transduction pathway, only mTNF triggers TNFR2 signaling (Probert 2015). TNF and its receptors also expressed outside the immune compartment, and notably in the CNS.
Evidence of the role of TNF in early neurodevelopment comes from studies in young mice. Slight increases in TNF levels are observed in the hippocampus and in the cortex during the first 2 postnatal weeks of life, a time of active neurogenesis and synaptogenesis (Garay et al. 2013). Moreover, low doses of TNF promoted the survival, proliferation, and neuronal differentiation mouse neonatal neural precursor cells cultures, while higher doses were apoptotic (Bernardino et al. 2008). Furthermore, young Tnf-knockout (KO) mice exhibit an accelerated maturation of the dentate gyrus hippocampal region, but with pyramidal neurons harbouring a smaller dendritic arborisation in CA1 and CA3 regions (Golan et al. 2004). Finally, both in vitro and in vivo studies have shown that developing pyramidal neurons from the cortex of Tnf-KO mice are deficient in synaptic scaling, a form of homeostatic plasticity that enables adjustment of synaptic strength at the neuron-scale in response to sustained activity, which is critical for the activity-dependent refinement of neural circuitry during early development (Stellwagen and Malenka 2006; Kaneko et al. 2008; Ranson et al. 2012) . This suggests a critical role for TNF in shaping the nervous system during early developmental stages.

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Human studies supporting a role of cytokines in neurodevelopment

Although many studies link disrupted patterns of cytokines with neurodevelopmental conditions (see next section 3.), some have identified both deleterious and beneficial links between the levels of specific gestational cytokines and neurocognitive behaviour in the general population. Gestational cytokine levels and neurocognitive behaviour: To assess the influence of maternal cytokine levels on offspring neurocognitive development, one study studied the association between maternal serum cytokine levels (measured longitudinally during the 2nd and 3rd trimesters of pregnancy) and neurocognitive outcme in the offspring at 7 years of age. The authors first estimated the cumulative exposure to each cytokine and then studied the associations with neurocognitive outcomes at 7 years. Among the cytokines assessed, they found two pro-inflammatory cytokines – TNF and IL-8 – to be associated with negative or positive neurocognitive outcomes, respectively. TNF was associated with problems in visual-motor functioning and lower cognitive scores, whereas IL-8 was associated with better cognitive performance and motor functioning (Ghassabian et al. 2018). While association does not necessarily imply causation, this study draws attention to the possible involvement maternal cytokines in neurodevelopmental processes at early life stages.
Another study investigated whether the socioeconomic environment can influence maternal immune activity during gestation and whether this was associated with adverse behavioural outcome in the offspring during the first year of life (Gilman et al. 2017). Several proinflammatory cytokines were measured in the maternal serum during the 3rd trimester of pregnancy. They found that gestational levels of IL-8 were lower in the most disadvantaged pregnancies experiencing more social-economic distress. Furthermore, maternal socio-economic disadvantage was associated with higher risk of structural and sensorimotor-related neurological abnormalities in the offspring. Finally, they found that decreased maternal IL-8 levels in disadvantaged pregnancies were positively associated with increased risk of neurological abnormalities. Together with previous studies reviewed in Hantsoo et al., 2018, this study suggests the involvement of maternal stress response to adversity, which can translate into maternal immune dysregulation and contribute to increase the offspring’s vulnerability to neuropsychiatric disorders.
The following figure (Illustration 5) provides more insight into the link between maternal stressors during pregnancy, which include immune dysfunction, and offspring neuropsychiatric development.

Human studies: the case of ASD

Maternal immune activation as a risk factor for ASD: One important environmental factor associated with an increased risk of neurodevelopmental disorders is maternal infection during pregnancy. Many studies have suggested that maternal exposure to various immune stimuli, such as viral and bacterial infections, is associated with abnormal brain development and mental illness in the offspring, particularly schizophrenia and schizophrenia-like disorders (Illustration 7).
There is evidence of other classes of pathogens being able to affect offspring neurodevelopment upon gestational exposure, namely rubella, toxoplasma and maternal genital or reproductive infections (Brown et al. 2001; Brown and Susser 2002; H. J. Sørensen et al. 2009; Penner and Brown 2007; Hyman, Arndt, and Rodier 2005). Moreover, maternal infection was also found to be associated with autism diagnosis in the offspring. This was first described in a group of children with congenital rubella in the wake of the 1964 US rubella pandemic (Chess 1971). Another study on the impact of congenital infections with Cytomegalovirus and autism diagnosis confirmed the initial association (Stubbs, Ash, and Williams 1984). This effect is now known to be due, not to the exact pathogen, but rather to the intensity of the maternal immune activation (MIA), which occurred during pregnancy (Shi 2003; Patterson 2009; Myka L.Estes 2016). Indeed, prenatal fever or hospitalization following infection, rather than the type of the infection per se, was associated with increased ASD risk (Hornig et al. 2018; Atladóttir et al. 2010).

Table of contents :

Table of contents
List of abbreviations
Introduction
1. Interactions between the immune system and the brain during immune activation 
1.1. Overview
1.2. Cytokines and cytokine receptors
1.3. Pathogen recognition
1.4. Pathogen Associated Molecular Patterns
1.5. The peripheral immune system and the brain
1.6. Cytokines and behaviour
2. How cytokines shape neurodevelopment
2.1. The essential role of cytokines during embryonic development
2.2. Microglia: neuroimmune interactions in shaping neuronal circuitry
2.3. Neonatal immune system vs. adult immune system
2.4. The essential role of cytokines during postnatal development
2.5. Specific role of cytokines in neurodevelopment: the example of TNF
2.6. Human studies supporting a role of cytokines in neurodevelopment
3. Cytokines can interfere with neurodevelopment and contribute to neurodevelopmental disorders, including autism spectrum disorders
3.1. Neurodevelopmental disorders – overview
3.2. Autism spectrum disorders
3.3. Human studies: the case of ASD
3.4. Mouse models of neurodevelopmental defects triggered by immune activation
4. Scientific hypotheses and objectives
Manuscript #1
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions & future directions
References
Figures
Manuscript #2
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions
References
Figures
Discussion
Overview
1. How does TNF impact neurodevelopment?
2. What is the physiological relevance of our experimental model in which pups are injected with recombinant TNF?
3. Vulnerability vs. resilience to psychological stress
4. What else could we do to further investigate the impact of TNF on neurodevelopment?
5. What is the impact of poly(I:C) injection on pregnant dams?
6. Why do pups born to poly(I:C)-injected mothers gain weight more rapidly than control pups?
7. Why do pups born to poly(I:C)-injected mothers exhibit communication impairment?
8. Why do pups born to poly(I:C)-injected mothers exhibit decreased locomotor activity?
9. Why did we analyse our data using a multivariable statistical approach, and which conclusions could we draw?
10. What is known about the role of TNF, CXCL10, IL-5 and IL-15 in neurodevelopment and brain function?
Take home message
References

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