title: IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury.
abstract: Macrophages and microglia play a key role in the maintenance of nervous system homeostasis. However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48 hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution-phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments. GLIA 2016;64:2079-2092.
authors.affiliation: Departament De Biologia Cel·lular, Fisiologia I Immunologia, Institut De Neurociències, Centro De Investigación Biomédica En Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma De Barcelona, Bellaterra, Catalonia, 08193, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Francos-Quijorna
authors.affiliation: Departament De Biologia Cel·lular, Fisiologia I Immunologia, Institut De Neurociències, Centro De Investigación Biomédica En Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma De Barcelona, Bellaterra, Catalonia, 08193, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Amo-Aparicio
authors.affiliation: Departament De Biologia Cel·lular, Fisiologia I Immunologia, Institut De Neurociències, Centro De Investigación Biomédica En Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma De Barcelona, Bellaterra, Catalonia, 08193, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Martinez-Muriana
authors.affiliation: Departament De Biologia Cel·lular, Fisiologia I Immunologia, Institut De Neurociències, Centro De Investigación Biomédica En Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma De Barcelona, Bellaterra, Catalonia, 08193, Spain. ruben.lopez@uab.cat.
authors.forename: Rubèn
authors.initials: R
authors.lastname: López-Vales
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D001119:Arginase; D016207:Cytokines; D015847:Interleukin-4; D052247:Nitric Oxide Synthase Type II; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C544448:Arg1 protein, mouse
keywords: IL-4; macrophage; neuroprotection; polarization; spinal cord injury