Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

Barron, Jerika J.; Mroz, Nicholas M.; Taloma, Sunrae; Dahlgren, Madelene W; Ortiz-Carpena, Jorge F.; Dorman, Leah C.; Vainchtein, Ilia D.; Escoubas, Caroline C.; Molofsky, Ari B.; Molofsky, Anna V.

doi:10.1101/2023.03.16.532850

Cited by 4 publications

(3 citation statements)

References 67 publications

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“…Both IL-4 and its receptors are expressed in the brain in neurons, oligodendroglia, astrocytes and microglia, and IL-4R expression increases after ischemic stroke indicative of a neuroprotective role (Amo-Aparicio et al, 2021; Bozinov et al, 2008; Fenn, Henry, Huang, Dugan, & Godbout, 2012; Lee, Koh, Lo, & Marchuk, 2018; T. F. Liu et al, 2003). About 25 % of neurons express IL-4RA, and an essential role of IL-4/IL-13 in the formation of inhibitory cortical synapses for normal social behavior is emerging for which a postsynaptic location of IL-4RA and IL-13RA1 is anticipated (Barron et al, 2023). In models of CNS injury, IL-4 protects neurons and induces recovery of injured neurons through neuronal IL-4RA (Walsh et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

IL-4 shaping glutamatergic synapse like structures for more mature iPSC derived neuron phenotypes

Zimmermann,

Schöpf,

Kern

et al. 2023

Preprint

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The prototypical pleiotropic anti-inflammatory cytokine IL-4 not only acts on immune cells but also has important roles in the nervous system mediating antinociception and neuroregeneration. Therefore, we explored the expression of IL-4, its receptors IL4RA and IL13RA1 and downstream signaling components together with morphological and functional assays as well as transcriptomic profiling in human nociceptors differentiating from induced pluripotent stem cells (iNocs).IL-4 induced de novo formation of synaptic boutons immunoreactive for vesicular glutamate transporter vGLUT1 in iNocs which express both, components of the IL-4 receptor complex (IL-4RA and IL-13RA1) and signaling machinery (Jak1/2, STAT6, PKC isoforms, translation factor EiF4E) during differentiation. Pharmacological inhibition of these translational or cellular signaling components reduced the synaptogenic effect. IL-4 induced distinct transcriptomic changes associated with biological process ontologies for “neuron projection development”, “axonogenesis” and “synapse”, “cellular process involved in reproduction in multicellular organism”, “regulation of membrane potential” and “calcium ion transmembrane transport”. This partially reflected injury-induced transcriptional changes of mouse nerve injury models which contribute to regenerative processes in peripheral nerve but possibly also to reconnecting primary afferent neurons to their projections in the spinal dorsal horn and indicates a critical role for IL-4 in the control of developing and established neuronal networks.

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Section: Discussionmentioning

confidence: 99%

IL-4 shaping glutamatergic synapse like structures for more mature iPSC derived neuron phenotypes

Zimmermann,

Schöpf,

Kern

et al. 2023

Preprint

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“…Although the basis for the difference between lung and meningeal ILC2s is unclear, lung ILC2s are exposed to far more environmental stimuli than meningeal ILC2s, likely leading to these transcriptional differences. A recent study reported that during development, meningeal ILC2s are required for cortical inhibitory synapse maturation and adult social behavior ( Barron et al, 2023 ). This function of ILC2 seems to be dependent on IL-13-production.…”

Section: Innate Lymphoid Cells In the Cnsmentioning

confidence: 99%

Innate lymphoid cells in neuroinflammation

Kveštak,

Mihalić,

Jonjić

et al. 2024

Front. Cell. Neurosci.

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Innate lymphoid cells (ILCs) are largely tissue-resident cells that participate in the maintenance of tissue homeostasis and react early to inflammatory events. Mature ILCs are divided into three major groups based on the transcription factors required for their development and function. Under physiological conditions, ILCs are present within the choroid plexus and meninges while the CNS parenchyma is almost devoid of these cells. However, pathological conditions such as autoimmune neuroinflammation and viral infections of the CNS result in the infiltration of ILCs into parenchyma. In this article, we provide an overview of the involvement and function of the ILCs within the CNS during physiological conditions and in infections, autoimmune diseases, neurodegeneration, and injury.

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“…The release of IFN-γ by T lymphocytes is also implicated in synaptic elimination by microglia and cognitive sequelae, as illustrated by spatial learning deficits in an animal model of flavivirus infection [78]. Also, a subset of innate lymphocytes is involved in cortical inhibitory synapse formation with impacts on social behavior development [79]. This may have important implications in the recent context of COVID-19, where the mechanisms associated with the long-term cognitive sequelae of Long COVID are still under investigation.…”

Section: Microglial and Neuroplasticity: Impact On Neurological Outco...mentioning

confidence: 99%

The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond

Chagas,

Serfaty

2024

IJMS

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Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults.

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Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

Cited by 4 publications

References 67 publications

IL-4 shaping glutamatergic synapse like structures for more mature iPSC derived neuron phenotypes

IL-4 shaping glutamatergic synapse like structures for more mature iPSC derived neuron phenotypes

Innate lymphoid cells in neuroinflammation

The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond

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