Abstract
Microglia play diverse roles in homeostasis and pathology of the central nervous system (CNS). Their response to injury or insult is critical for initiating neuroinflammation and tissue damage as well as resolution of inflammation and wound healing. Changes to the microenvironment of microglia appear to be a key determinant of their phenotype and their role in the endogenous repair process in the injured or diseased CNS. Our recent findings have identified a positive role for neuregulin-1 (Nrg-1) in regulating immune response in spinal cord injury and focal demyelinating lesions. We show that increasing the tissue availability of Nrg-1 after injury can promote endogenous repair by modulating neuroinflammation. In the present study, we sought to elucidate the specific role of Nrg-1 in regulating microglial activity and more importantly their influence on the behavior of neural stem/progenitor cells (NPCs). Using injury-relevant in vitro systems, we demonstrate that Nrg-1 attenuates the expression of proinflammatory mediators in activated microglia. Moreover, we provide novel evidence that availability of Nrg-1 can restore the otherwise suppressed phagocytic ability of proinflammatory microglia. Interestingly, the presence of Nrg-1 in the microenvironment of proinflammatory microglia mitigates their inhibitory effects on NPC proliferation. Nrg-1 treated proinflammatory microglia also augment mobilization of NPCs, while they had no influence on their suppressive effects on NPC differentiation. Mechanistically, we show that Nrg-1 enhances the interactions of proinflammatory microglia and NPCs, at least in part, through reduction of TNF-α expression in microglia. These findings provide new insights into the endogenous regulation of microglia-NPC interactions and identify new potential targets for optimizing this important crosstalk during the regenerative process after CNS injury and neuroinflammatory conditions.
Highlights
Microglia play critical roles in the normal and pathologic central nervous system (CNS)
We confirmed the expression of all Nrg-1 receptors in our microglial culture using coimmunostaining of OX42 with ErbB2, ErbB3, and ErbB4 (Supplementary Figures 1a–1i)
We found a significant 7.2-fold increase in the mRNA level of cluster of differentiation 86 (CD86) in proinflammatory microglia, which was significantly reduced by 65% with Nrg-1 treatment at 200 ng/ml compared to nontreated proinflammatory microglia (p < 0 0001, one-way analysis of variance (ANOVA), N = 4 independent cultures) (Figure 2(e))
Summary
Microglia play critical roles in the normal and pathologic central nervous system (CNS). Microglia play pivotal roles in neuroinflammation and innate immune response in neuropathological conditions including neurotrauma, neurodegenerative diseases, stroke, and multiple sclerosis (MS) [7,8,9,10]. Microglia rapidly respond and polarize toward classical proinflammatory or alternative anti-inflammatory or proregenerative phenotypes [11]. Proinflammatory microglia increase their production of proinflammatory cytokines and mediators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, reactive oxygen species (ROS) and nitric oxide (NO), and cluster of differentiation 86 (CD86) receptors, which promote neuroinflammation and tissue damage [12, 13]. Proregenerative microglia secrete several anti-inflammatory mediators such as transforming growth factor-β (TGF-β), IL-10, and arginase-1 (Arg-1), which facilitate the resolution of inflammation and support phagocytosis of tissue debris
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