Heterogeneous induction of microglia M2a phenotype by central administration of interleukin-4

Abstract

BackgroundAcquisition of the M1 or M2 phenotypes by microglia has been shown to occur during the development of pathological conditions, with M1 activation being widely involved in neurotoxicity in relation with the anatomical localization and the reactivity of subtypes of microglia cells. On the contrary, little is known on the ability of microglia to undergo M2 polarization by interleukin-4 (IL4), the typical M2a polarization signal for peripheral macrophages.MethodsRecombinant mouse IL4 was injected in the third cerebral ventricle of mice to induce brain alternative polarization. The mRNA levels of Fizz1, Arg1, and Ym1 genes, known to be up-regulated by IL4 in peripheral macrophages, together with additional polarization markers, were evaluated in the striatum and frontal cortex at different time intervals after central administration of IL4; in parallel, M2a protein expression was evaluated in tissue extracts and at the cellular level.ResultsOur results show that the potency and temporal profile of IL4-mediated M2a gene induction vary depending on the gene analyzed and according to the specific brain area analyzed, with the striatum showing a reduced M2a response compared with the frontal cortex, as further substantiated by assays of polarization protein levels. Of notice, Fizz1 mRNA induction reached 100-fold level, underscoring the potency of this specific IL4 signaling pathway in the brain. In addition, immunochemistry assays demonstrated the localization of the M2 response specifically to microglia cells and, more interestingly, the existence of a subpopulation of microglia cells amenable to undergoing M2a polarization in the healthy mouse brain.ConclusionsThese results show that the responsiveness of brain macrophages to centrally administered IL4 may vary depending on the gene and brain area analyzed, and that M2a polarization can be ascribed to a subpopulation of IL4-responsive microglia cells. The biochemical pathways that enable microglia to undergo M2a activation represent key aspects for understanding the physiopathology of neuroinflammation and for developing novel therapeutic and diagnostic agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0211-6) contains supplementary material, which is available to authorized users.

Differential response to intrahippocampal interleukin-4/interleukin-13 in aged and exercise mice

“…However, less is known about how aging affects the induction of an anti-inflammatory M2 response. The present data confirm that infusion of the anti-inflammatory cytokines IL-4 and IL-13 induces expression of the M2-associated genes, namely, Arg1, Fizz1, CD206, SOCS1, Ym1, TGF-β, and IL-1ra (Butovsky et al, 2005, Cecilio et al, 2011, Pepe et al, 2014). However, the animal’s age modulated this response, as aged mice showed increased hippocampal expression of Arg1, CD206, SOCS1, and Ym1 in response to IL-4/IL-13 administration relative to adults.…”

“…In contrast, microglia are also capable of expressing an alternative or M2 phenotype. This activation state is neuroprotective, characterized by the release of anti-inflammatory molecules including IL-4, IL-13, and IL-10 as well as neurotrophic factors and is thought to promote healing through the resolution of inflammation (Mosser, 2003, Ponomarev et al, 2007, Pepe et al, 2014). Additionally, the M2 phenotype increases levels of arginase-1 (Arg1) which contributes to wound healing and matrix deposition, chitinase-like 3 (Ym1), found in inflammatory zone 1 (Fizz1) which promotes deposition of the extracellular matrix, and CD206 a mannose receptor (Cherry et al, 2014).…”

Switching on microglia with electro-conductive multi walled carbon nanotubes

“…Recent studies have shown that, in response to certain environmental toxins, endogenous proteins and bacterial or viral signals microglia can enter in an over activated state and release neurotoxic and pro-inflammatory factors, including nitric oxide (NO) [28], inflammatory cytokines, such as interleukin-1b (Il-1b), tumor necrosis factor-a (TNF-a), reactive oxygen species (ROS) [29], and glutamate [30]. Microglia can also undergo the alternative M2 phenotype as a consequence of parasite invasion and in response to endogenous immune signals, in order to provide tissue repair and resolution of inflammation [31]. Recently, emerging lines of evidence indicate that physiological functions of microglia play a key role in the regulation of CNS activity, impact neuronal circuitry and network connectivity, and contribute to neuronal plasticity [21,28].…”

Role for microglia in sex differences after ischemic stroke: importance of M2

“…In particular, in vitro stimulation with lipopolysaccharide and interferon-γ (IFN-γ) promotes the differentiation of “classically activated” M1 microglia/macrophages that typically leads to release of destructive pro-inflammatory mediators (Rosenzweig and Carmichael 2013). In contrast, interleukin (IL)-4 (Pepe et al 2014; Xiong et al 2011) and IL-10 induce an “alternatively activated” M2 phenotype that possesses neuroprotective properties (Chu et al 2012; Jalal et al 2012; Wang et al 2013). Typically, the damaged tissue environment in vivo immediately after stroke attracts neutrophils and promotes an M1 phenotype (Hu et al 2012), including M1 microglia and recruited peripheral macrophages, that increase inflammation and cell death beyond the initial ischemic infarct (Denker et al 2007; Schilling et al 2005).…”