The plasticity of primary microglia and their multifaceted effects on endogenous neural stem cells in vitro and in vivo

Abstract

BackgroundMicroglia—the resident immune cells of the brain—are activated after brain lesions, e.g., cerebral ischemia, and polarize towards a classic “M1” pro-inflammatory or an alternative “M2” anti-inflammatory phenotype following characteristic temporo-spatial patterns, contributing either to secondary tissue damage or to regenerative responses. They closely interact with endogenous neural stem cells (NSCs) residing in distinct niches of the adult brain. The current study aimed at elucidating the dynamics of microglia polarization and their differential effects on NSC function.ResultsPrimary rat microglia in vitro were polarized towards a M1 phenotype by LPS, or to a M2 phenotype by IL4, while simultaneous exposure to LPS plus IL4 resulted in a hybrid phenotype expressing both M1- and M2-characteristic markers. M2 microglia migrated less but exhibit higher phagocytic activity than M1 microglia. Defined mediators switched microglia from one polarization state to the other, a process more effective when transforming M2 microglia towards M1 than vice versa. Polarized microglia had differential effects on the differentiation potential of NSCs in vitro and in vivo, with M1 microglia promoting astrocytogenesis, while M2 microglia supported neurogenesis. Regardless of their polarization, microglia inhibited NSC proliferation, increased NSC migration, and accelerated NSC differentiation.ConclusionOverall, this study shed light on the complex conditions governing microglia polarization and the effects of differentially polarized microglia on critical functions of NSCs in vitro and in vivo. Refining the understanding of microglia activation and their modulatory effects on NSCs is likely to facilitate the development of innovative therapeutic concepts supporting the innate regenerative capacity of the brain.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1261-y) contains supplementary material, which is available to authorized users.

Neuroprotective and Anti—Neuroinflammatory Effects of a Poisonous Plant Croton tiglium Linn. Extract

“…Astrocytes are the most abundant glia in the brain, and astrocytic activation also contributes to and expands the initial inflammatory response and neurodestructive effects of microglia [29,30]. Although initial studies on neuroinflammation suggested that microglial activation was detrimental to neurogenesis [31][32][33], more recent studies have proven the beneficial role of microglial activation on the regulation of the migration, proliferation, and differentiation of neural stem cells [34,35]. In particular, alternative activation of microglia (type M2) can increase neuroprotective factors such as nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 [36].…”

Dynamic Modelling of Interactions between Microglia and Endogenous Neural Stem Cells in the Brain during a Stroke

“…On the other hand, the microglia can also play a negative role, through secretion of damaging proinflammatory cytokines which increase inflammation in the area of healthy cells [5,17]. We consider the damage D caused by the activated microglia to represent secondary damage in the case of stroke [2,14]. The following differential equation describes this damage:…”

“…The harmful effects, which are toxic to tissues, occur primarily through the production of free radicals [12,13]. This reaction is important in removing damaged cells from the brain tissue; however, it can also increase the harm to brain cells by producing free radicals that are toxic to healthy cells [2,14,15]. There has been an increasing amount of evidence suggesting that ischemic inflammation may be vital to the issue of pathogens, as ischemic stroke results not only in damage and neuronal loss but also in sustained neuroinflammation after stroke [3,16,17].…”

Developmental dynamics of neurogenesis and gliogenesis in the postnatal mammalian brain in health and disease: Historical and future perspectives

“…As major immune-competent cells in the brain, microglia exert multiple functions under various physiological and pathological conditions (Wolf, Boddeke, & Kettenmann, 2017). Notably, recent studies have demonstrated that microglia regulate proliferation and differentiation of NSCs and OPCs either positively or negatively depending on conditions, thereby affecting the cellular dynamics of the postnatal brain in both the VZ-SVZ and DG (Kreisel, Wolf, Keshet, & Licht, 2018;Morton, Neckles, Seluzicki, Holmberg, & Feliciano, 2018;Naruse, Shibasaki, Shimauchi-Ohtaki, & Ishizaki, 2018;Vay et al, 2018;Walton et al, 2006). Yet, what impact microglia have on normal brain development remains to be further investigated.…”