Harnessing the Benefits of Neuroinflammation: Generation of Macrophages/Microglia with Prominent Remyelinating Properties.

Autor:	Mishra MK; Hotchkiss Brain Institute and Department of Clinical Neurosciences., Rawji KS; Hotchkiss Brain Institute and Department of Clinical Neurosciences., Keough MB; Hotchkiss Brain Institute and Department of Clinical Neurosciences., Kappen J; Hotchkiss Brain Institute and Department of Clinical Neurosciences., Dowlatabadi R; Department of Biological Sciences., Vogel HJ; Department of Biological Sciences., Chopra S; Department of Physiology & Pharmacology.; McCaig institute for Bone and Joint Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada., Distéfano-Gagné F; Department of Molecular Medicine, Université Laval, Quebec City, Quebec K2P 0J6, Canada., Dufour A; Department of Physiology & Pharmacology.; McCaig institute for Bone and Joint Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada., Gosselin D; Department of Molecular Medicine, Université Laval, Quebec City, Quebec K2P 0J6, Canada., Yong VW; Hotchkiss Brain Institute and Department of Clinical Neurosciences vyong@ucalgary.ca.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2021 Apr 14; Vol. 41 (15), pp. 3366-3385. Date of Electronic Publication: 2021 Mar 12.
DOI:	10.1523/JNEUROSCI.1948-20.2021
Abstrakt:	Excessive inflammation within the CNS is injurious, but an immune response is also required for regeneration. Macrophages and microglia adopt different properties depending on their microenvironment, and exposure to IL4 and IL13 has been used to elicit repair. Unexpectedly, while LPS-exposed macrophages and microglia killed neural cells in culture, the addition of LPS to IL4/IL13-treated macrophages and microglia profoundly elevated IL10, repair metabolites, heparin binding epidermal growth factor trophic factor, antioxidants, and matrix-remodeling proteases. In C57BL/6 female mice, the generation of M(LPS/IL4/IL13) macrophages required TLR4 and MyD88 signaling, downstream activation of phosphatidylinositol-3 kinase/mTOR and MAP kinases, and convergence on phospho-CREB, STAT6, and NFE2. Following mouse spinal cord demyelination, local LPS/IL4/IL13 deposition markedly increased lesional phagocytic macrophages/microglia, lactate and heparin binding epidermal growth factor, matrix remodeling, oligodendrogenesis, and remyelination. Our data show that a prominent reparative state of macrophages/microglia is generated by the unexpected integration of pro- and anti-inflammatory activation cues. The results have translational potential, as the LPS/IL4/IL13 mixture could be locally applied to a focal CNS injury to enhance neural regeneration and recovery. SIGNIFICANCE STATEMENT The combination of LPS and regulatory IL4 and IL13 signaling in macrophages and microglia produces a previously unknown and particularly reparative phenotype devoid of pro-inflammatory neurotoxic features. The local administration of LPS/IL4/IL13 into spinal cord lesion elicits profound oligodendrogenesis and remyelination. The careful use of LPS and IL4/IL13 mixture could harness the known benefits of neuroinflammation to enable repair in neurologic insults. (Copyright © 2021 the authors.)
Databáze:	MEDLINE
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