Targeted intracerebral delivery of the anti-inflammatory cytokine IL13 promotes alternative activation of both microglia and macrophages after stroke

Abstract

BackgroundSubtle adjustment of the activation status of CNS resident microglia and peripheral macrophages, to promote their neuroprotective and neuroregenerative functions, may facilitate research towards curing neurodegenerative disorders. In the present study, we investigated whether targeted intracerebral delivery of the anti-inflammatory cytokine interleukin (IL)13, by means of transplanting IL13-expressing mesenchymal stem cells (IL13-MSCs), can promote a phenotypic switch in both microglia and macrophages during the pro-inflammatory phase in a mouse model of ischemic stroke.MethodsWe used the CX3CR1eGFP/+ CCR2RFP/+ transgenic mouse model to separately recognize brain-resident microglia from infiltrated macrophages. Quantitative immunohistochemical analyses were applied to characterize polarization phenotypes of both cell types.ResultsDistinct behaviors of both cell populations were noted dependent on the anatomical site of the lesion. Immunohistochemistry revealed that mice grafted with IL13-MSCs, in contrast to non-grafted and MSC-grafted control mice, were able to drive recruited microglia and macrophages into an alternative activation state, as visualized by a significant increase of Arg-1 and a noticeable decrease of MHC-II expression at day 14 after ischemic stroke. Interestingly, both Arg-1 and MHC-II were expressed more abundantly in macrophages than in microglia, further confirming the distinct behavior of both cell populations.ConclusionsThe current data highlight the importance of controlled and localized delivery of the anti-inflammatory cytokine IL13 for modulation of both microglia and macrophage responses after ischemic stroke, thereby providing pre-clinical rationale for the application of L13-MSCs in future investigations of neurodegenerative disorders.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1212-7) contains supplementary material, which is available to authorized users.

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…However, in one study, administration of IL-13-producing MSCs modulated infiltrating immune cells to an M2-like state but not the resident cells in the surrounding pathological area caused by SE, 80 demonstrating that, in principle, exogenous IL-13 can influence microglial phenotypes. This aligns with other studies showing that MSCs delivering IL-13 are able to induce an M2 neuroprotective phenotype in a stroke model in mice, 72 and that viral vector-based delivery of IL-13 provides protection against cuprizone-induced demyelination, perhaps due to the observed polarization of microglia toward an M2 phenotype. 73 Regarding IL-4, a recent | 211…”

“…Despite some of these drugs having shown neuroprotective effects in animal models of brain disease, none has succeeded in clinical trials. Strategies promoting M2 activation of microglia and macrophages have shown improved pathological and functional outcomes in CNS diseases associated with acute or chronic neuroinflammation . Different strategies have been adopted to achieve this, including pharmacological treatment, cell delivery systems, and gene therapy, strategies that should be explored for the treatment and prevention of PTE (Table ).…”

“…Strategies promoting M2 activation of microglia and macrophages have shown improved pathological and functional outcomes in CNS diseases associated with acute or chronic neuroinflammation. [71][72][73] Different strategies have been adopted to achieve this, including pharmacological treatment, cell delivery systems, and gene therapy, strategies that should be explored for the treatment and prevention of PTE (Table 1). The outcomes of the studies discussed below may not be exclusively related to microglia/macrophage polarization but may be a complex interaction of inflammatory mediators released from these cells with the other cellular mediators of inflammation such as brain-resident astrocytes as well as the peripheral cells that migrate to the site of injury.…”

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

“…5D-F). Unfortunately, this corroborates many other attempts with genetically modified MSCs (49,63,65,67). Studies that saw an improvement typically saw a change in only one out of multiple assessments, or only looked at a single time point (63,64,66).…”

“…SOD2 overexpression demonstrated improved motor coordination at one timepoint tested after focal TBI (64). IL-13 overexpression promotes an M2-like phenotype, but it has only been observed to improve some functional assessments in an SCI model and failed to rescue function in stroke and epilepsy models (65)(66)(67). IL-10 overexpression from MSCs did not reduce TBI lesion volume or improve most functional assessments (47,49).…”