IL-4 Signaling Drives a Unique Arginase+/IL-1 + Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4R  after Traumatic Spinal Cord Injury

Fenn, Ashley M.; Hall, Jodie C. E.; Gensel, John C.; Popovich, Phillip G.; Godbout, Jonathan P.

doi:10.1523/jneurosci.1146-14.2014

Cited by 172 publications

(151 citation statements)

References 48 publications

(32 reference statements)

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“…Although IL-4 was not detected in the contused spinal cord, it is likely to be present at very low levels, as a previous study reported that IL-4Rα null mice show greater functional deficits after SCI (Fenn et al 2014). In the current work, however, we found that increasing the levels of IL-4 in the injured spinal cord by direct intraspinal injection of IL-4 induces the expression of M2 markers in microglia and macrophages.…”

Section: Discussionmentioning

confidence: 80%

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

Francos-Quijorna

Amo-Aparicio

Martínez-Muriana

2016

Glia

159

135

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"This is the peer reviewed version of the following article: Francos-Quijorna I, Amo-Aparicio J, Martinez-Muriana A, López-Vales R. IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair andfunctional recovery after spinal cord injury. Glia. 2016 Dec;64(12):2079-2092 ABSTRACTMacrophages 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, 48hours 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.

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Section: Discussionmentioning

confidence: 80%

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

Francos-Quijorna

Amo-Aparicio

Martínez-Muriana

2016

Glia

159

135

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“…An additional modulator for tissue repair and remodeling in the CNS injury is arginase-1. Studies indicated that arginase-1 expression is correlated with improved recovery from CNS injury and disease [80,[139][140][141]. A recent study using EAE and spinal cord injury models has shown that infiltrated macrophages mainly express arginase-1 in the inflamed CNS [142], suggesting the importance of infiltrated myeloid cells in the CNS repair after injury.…”

Section: Inflammation Versus Resolutionmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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“…IL-4 treatment of macrophages in vitro produced IL-6 and co-expressed CD206 (M2 marker) without affecting immunosuppressive properties of M2 phenotype macrophages (Casella et al 2016). Moreover, the expression of Arg-1 as well as IL-1β was associated with neurite growth promotion and spinal cord injury recovery (Fenn et al 2014). IL-4 gene therapy to EAE mice decreased demyelination and axonal loss showing an increase in the expression of CD206 in microglia/macrophages, but also an increase IL-6 (Casella et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies in vitro and in vivo have revealed that reactive microglia/macrophages are able to co-express M1 and M2 markers. In vivo experiments have shown that treatent of mice with LPS increases proinflammatory cytokines including IL-1β, but also IL-4R and further treatment with IL-4 induced the expression of Arg-1 as well as IL-1β, and this unique phenotype was able to promote neurite growth and spinal cord injury recovery (Fenn et al 2014). Furthermore, macrophages treated with IL-4 in vitro, were shown to produce IL-6 while co-expressing the M2 characteristic molecule CD206, and the co-expression of IL-6 did not affect immunosuppressive properties of the M2 phenotype macrophages (Casella et al 2016).…”

Section: Microglia/macrophage Activation Phenotypementioning

confidence: 99%

Mechanisms Involved in the Remyelinating Effect of Sildenafil

Díaz-Lucena

Gutièrrez‐Mecinas

Moreno

et al. 2017

J Neuroimmune Pharmacol

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ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials dʼinvestigació i docència en els termes establerts a lʼart. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix lʼautorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No sʼautoritza la seva reproducció o altres formes dʼexplotació efectuades amb finalitats de lucre ni la seva comunicació pública des dʼun lloc aliè al servei TDX. Tampoc sʼautoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral. No se autoriza su reproducción u otras formas de explotación efectuadas con fines lucrativos ni su comunicación pública desde un sitio ajeno al servicio TDR. Tampoco se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al contenido de la tesis como a sus resúmenes e índices.WARNING.

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IL-4 Signaling Drives a Unique Arginase+/IL-1 + Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4R after Traumatic Spinal Cord Injury

Cited by 172 publications

References 48 publications

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

Microglia and Monocyte-Derived Macrophages in Stroke

Mechanisms Involved in the Remyelinating Effect of Sildenafil

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