Attraction and role of innate immune cells in brain injury
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Attracting Innate Lymphoid Cells to stroke. Brain injury is inflicted after stroke and many patients suffer from ill-repaired brain lesions after this event. Chemokine CXCL12 has been implicated in reorganization of damaged tissues including brain. It is expressed in cerebral vascular endothelial cells and is dramatically upregulated within the region of a brain injury. Although many immune cells expressing the CXCL12 receptor CXCR4 are attracted towards brain lesions, a causal relationship between cerebral CXCL12 and immune cell recruitment has not been established. Here, we focus on innate immune cells expressing CXCR4, namely innate lymphoid cells (ILCs) in this project and bone marrow-derived macrophages (BMdM) in the partnering project of the PRC International funded study. ILCs have been recently described and have important roles in maintenance of health. They are tissue resident cells, but in steady-state almost none are observed within the brain. Moreover, there is almost nothing known on their presence and role in brain injury. The objective of this project was to map spatial and temporal patterns of innate immune cell recruitment to sites of primary and secondary damage after focal ischemic brain injury. We addressed whether the attraction of innate immune cells such as monocytes and ILCs by CXCL12 towards the affected tissue is beneficial or detrimental for recovery. The role of Cxcl12 in the attraction of ILCs to stroke using specific mouse models. We established several genetic mouse models to interfere with the CXCL12/CXCR4 pathway in cell populations of interest. With these unique tools, we have studies spatial and temporal patterns of innate immune cell recruitment, interaction of innate immune cells and the role of CXCL12 in damage and functional recovery in established models of focal cerebral ischemia. The presence of the ILCs was assessed at different intervals during the stroke recovery to establish when they would arrive and have a role in the recovery. Project main results: Here, we report that ILCs are not resident within the mouse brain parenchyma during steadystate conditions, but are attracted after ischemic stroke. Specifically, we identified NK cells, ILC1s, ILC2s and ILC3s within the lesion, the highest influx being observed for NK cells and ILC1s. We further show that Cxcl12 expressed at the blood-brain barrier is essential for NK cells and NKp46+ ILC3s to migrate toward the lesion. Complementary, Cxcr4-deficiency in NK cells prevented NK cells from entering the infarct area. The lack of NK cell migration resulted in a higher neurological deficit in the beam-walk sensorimotor test. Our data show a new role for blood-brain barrier-derived Cxcl12 in attracting protective NK cells to ischemic brain lesions and identifies a new Cxcl12/ Cxcr4-mediated component of the innate immune response to stroke.
Publications
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CXCL12‐mediated feedback from granule neurons regulates generation and positioning of new neurons in the dentate gyrus. Glia, 66(8), 1566-1576.
Abe, Philipp; Wüst, Hannah M.; Arnold, Sebastian J.; van de Pavert Serge, A. & Stumm, Ralf
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Distinct Waves from the Hemogenic Endothelium Give Rise to Layered Lymphoid Tissue Inducer Cell Ontogeny. Cell Reports, 32(6), 108004.
Simic, Milesa; Manosalva, Iris; Spinelli, Lionel; Gentek, Rebecca; Shayan, Raheleh R.; Siret, Carole; Girard-Madoux, Mathilde; Wang, Shuaiwei; de Fabritus, Lauriane; Verschoor, Janneke; Kerdiles, Yann M.; Bajenoff, Marc; Stumm, Ralf; Golub, Rachel & van de Pavert Serge, A.
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1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development. Developmental Cell, 56(22), 3128-3145.e15.
Wang, Ting; Wang, Zheng; de Fabritus, Lauriane; Tao, Jinglian; Saied, Essa M.; Lee, Ho-Joon; Ramazanov, Bulat R.; Jackson, Benjamin; Burkhardt, Daniel; Parker, Mikhail; Gleinich, Anne S.; Wang, Zhirui; Seo, Dong Eun; Zhou, Ting; Xu, Shihao; Alecu, Irina; Azadi, Parastoo; Arenz, Christoph; Hornemann, Thorsten ... & Santori, Fabio R.
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Innate Lymphoid Cells in the Central Nervous System. Frontiers in Immunology, 13.
Wang, Shuaiwei & van de Pavert Serge, A.
