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A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model.

Abstract (Expand)

Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted … a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule alpha4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4(+) T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4(+) T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions.

Authors: A. Kendirli, C. de la Rosa, K. F. Lammle, K. Eglseer, I. J. Bauer, V. Kavaka, S. Winklmeier, L. Zhuo, C. Wichmann, L. A. Gerdes, T. Kumpfel, K. Dornmair, E. Beltran, M. Kerschensteiner, N. Kawakami

Date Published: 4th Oct 2023

Publication Type: Journal

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Abstract (Expand)

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here … we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Authors: Y. H. Tai, D. Engels, G. Locatelli, I. Emmanouilidis, C. Fecher, D. Theodorou, S. A. Muller, S. Licht-Mayer, M. Kreutzfeldt, I. Wagner, N. P. de Mello, S. N. Gkotzamani, L. Trovo, A. Kendirli, A. Aljovic, M. O. Breckwoldt, R. Naumann, F. M. Bareyre, F. Perocchi, D. Mahad, D. Merkler, S. F. Lichtenthaler, M. Kerschensteiner, T. Misgeld

Date Published: 25th Aug 2023

Publication Type: Journal

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