Ecto-5′-nucleotidase (CD73) attenuates inflammation after spinal cord injury by promoting macrophages/microglia M2 polarization in mice

Abstract

BackgroundImmune activation, specifically activation of macrophages and resident microglia, leading to inflammation is a key component in the progression of spinal cord injury (SCI). Macrophages/microglia exist in two states—the classically activated M1 phenotype that confers pro-inflammatory effects or the alternatively activated M2 phenotype that confers anti-inflammatory effects. Ecto-5′-nucleotidase (CD73) is an immunosuppressive molecule intricately involved in adaptive and innate immune responses and is able to dephosphorylate AMP to adenosine. However, it is not known if CD73 is able to modulate the macrophages/microglia transformation between the M1 and M2 phenotypes.MethodsWe used gene-deficient mice to determine the role of CD73 in macrophages/microglia polarization post-SCI in vivo. We used small interference RNA (siRNA) or pcDNA3.1 to inhibit or overexpress CD73 in BV2 cells to verify anterior discovery in vitro. A combination of molecular and histological methods was used to detect the macrophages/microglia polarization and explore the mechanism both in vivo and in vitro.ResultsWe found that SCI induced the upregulation of CD73 expression. CD73 deficient mice were noted to demonstrate overwhelming immune responses, few anti-inflammatory phenotype macrophages/microglia, and had a poorer locomotor recovery in comparison to wild-type mice that were also inflicted with SCI. In vitro studies found that CD73 suppression inhibited the expression of characteristic microglial anti-inflammatory polarization markers in BV2 cells, while the converse was noted in CD73 overexpression. Subsequent experiments confirmed that CD73 promoted microglia alternative activation by stimulating p38 MAPK.ConclusionWe were able to conclude that CD73 imparts neuroprotective effects by mediating macrophages/microglia polarization. These findings allow for better understanding of the modulatory factors involved in triggering the change in macrophages/microglia phenotypes, therefore uncovering additional molecules and pathways that may be targeted in the innovation of novel SCI therapies.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1183-8) contains supplementary material, which is available to authorized users.

BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats

“…12,17 To evaluate the pro-inflammatory microenvironment after SCI, we detected the levels of TNF-α, IL-β and IL-6 in injured spinal cord. 17,20 To test BRD4 activation in microglia after SCI, we collected the T7-T10 level around the lesion part of the spinal cord to detect the gross level of BRD4 in the spinal cord. It is reported that BRD4 is implicated with pro-inflammatory phenotypes in various cell types and microglia play a critical role in inflammatory response in the central nervous system.…”

“…It is reported that BRD4 is implicated with pro-inflammatory phenotypes in various cell types and microglia play a critical role in inflammatory response in the central nervous system. 17,20 To test BRD4 activation in microglia after SCI, we collected the T7-T10 level around the lesion part of the spinal cord to detect the gross level of BRD4 in the spinal cord. Despite the sudden reduction at 1 hour after SCI, the level of BRD4 was increased after 1 hour of SCI, coinciding with the gradually elevated production of pro-inflammatory cytokines at the early stage of SCI, which indicated that BRD4 might be enhanced in microglia and induced inflammatory response after SCI ( Figure 1D,E).…”

Low‐level laser therapy 810‐nm up‐regulates macrophage secretion of neurotrophic factors via PKA‐CREB and promotes neuronal axon regeneration in vitro

“…play key roles in both time and space in the physiological microenvironment. 15 Increasing numbers of studies have shown that macrophages have different polarization states in different environments. M1 macrophages promote the secretion of proinflammatory factors and are neurotoxic, whereas M2 macrophages can suppress the inflammatory reaction and promote axonal growth.…”

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

“…As in therapeutic interventions for many diseases, G protein‐coupled receptors (GPCRs) appear as potential targets to skew microglial phenotype. Recent results suggest an important potential of microglial adenosine receptors in neuroprotection because expression of CD73, the ectoenzyme that produces extracellular adenosine, attenuates inflammation by promoting M2 polarization (Xu et al, ). Among the four subtypes of adenosine receptors, the A 2A is the most promising in neuroprotection (see (Franco & Navarro, ) for review).…”