Understanding the role of meningeal macrophages on neurogenesis in physiological or pathological (inflammatory) conditions

Description

The meninges represent a tissue enveloping the brain. Recent data, including from our team, revealed that they contain a large panel of resident immune cells that can have a detrimental role in neuroinflammation (1,2). Early-life inflammation correlates with an increased risk of developing neurological disorders, including autism. Studies in rodents have shown that perinatal inflammation can lead to cytokine signaling in brains of neonates, abnormal neurodevelopment and social behavior. The meninges represent an immunologically active site, at the interface between the brain and the periphery. Because the meninges could be a relay and amplify inflammation, we hypothesize that they could play a major role in inflammation-induced neurodevelopmental disorders.
However, meningeal immune cells can also have a beneficial role in brain functions and promote social and cognitive behavior in the adult (3). Whether this positive action on the brain also occurs in early-life and whether it can help brain development and growth is unknown. Interestingly, the meninges and their resident immune cells (especially macrophages) penetrate the brain parenchyma between substructures, including the hippocampus which is an important neurogenic niche. In this line, the objective of this M2 project is to investigate whether meningeal macrophages could influence developmental neurogenesis in physiological (Laurie Arnaud-Paroutaud supervision) and/or pathological (inflammatory condition) (Narjess Haidar supervision).
We hypothesize that meningeal macrophages could act on developmental neurogenesis through the liberation of specific factors. To address this question, we will combine multiple chemical and genetic innovative models to deplete macrophages, and analyze neurogenic output with RT-qPCR, immunohistochemistry and an original in vitro approaches of meningeal explant co-culture with neurospheres developed in the team. We will also perform behavioral experiments in macrophage-depleted mice.

Selection of recent publications 1–3
1. Kwang and Rua, et al. T-bet-dependent NKp46 + innate lymphoid cells regulate the onset of T H 17-induced neuroinflammation, 2017, Nature Immunology
2. Rua R, et al. Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nature Immunology (2019)
3. Herz J, et al. GABAergic neuronal IL-4R mediates T cell effect on memory. Neuron. 2021

Eme-Scolan E, Arnaud-Paroutaud L, Haidar N, Roussel-Queval A & Rua R. Meningeal regulation of infections: A double-edged sword. European Journal of Immunology (2023).
Roussel-Queval A, Rebejac J, Eme-Scolan E, Paroutaud L & Rua R. Flow cytometry and immunohistochemistry of the mouse dural meninges for immunological and virological assessments. STAR Protocols (2023).
Rebejac J, Eme-Scolan E, […] and Rua, R. Meningeal macrophages protect against viral neuroinfection. Immunity (2022)
Mikhailov N, Virenque A, Koroleva K, Eme-Scolan E, […], Rua R, Noe FM, Giniatullin R. The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception. Scientific Reports (2022)
Rua R, Pujol N. IL-17: good fear no tears. Nat Immunol comments (2020)
Rua R, McGavern DB. Advances in Meningeal Immunity. Cell Press Trends Mol Med (2018)

Desired profile

M2 Neurosciences

Host institution

The student will join a young and dynamic team (ERC laureate) consisting of 1 researcher, 2 post-docs, 2 engineers, 4 PhD students, and will be supervised by Laurie Arnaud-Paroutaud (Post-doc) or Narjess Haidar (PhD) and Rejane Rua (PI, former ENS student). The CIML institute, located at the entrance of the Parc National des Calanques, stands as a leading immunology institute in France, with approximately 250 members and offering access to essential equipment, including state-of-the-art microscopes, cytometers, and genomic facilities.