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.
Highlights
Subtle adjustment of the activation status of Central nervous system (CNS) resident microglia and peripheral macrophages, to promote their neuroprotective and neuroregenerative functions, may facilitate research towards curing neurodegenerative disorders
The present study demonstrates that brain-resident microglia and infiltrated macrophages accumulate in the post-ischemic brain with distinct spatial patterns, indicating that they act as functionally different populations in CNS injury
We focused on addressing important applications of interleukin 13 (IL13)-expressing mesenchymal stem/ stromal cells (MSCs) as a new potential therapeutic approach for ischemic stroke
Summary
Subtle 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. Under inflammatory condition caused by ischemia, there is a complex interaction between brain-resident microglia and infiltrated macrophages These two phagocytic cell populations share many antigenic markers, rapidly growing literature on this subject indicates that both cell types have distinct specialized functions [3, 4]. We performed stroke experiments in CX3CR1eGFP/+ CCR2RFP/+ knock-in fluorescent protein reporter mice, in order to distinguish brain-resident microglia from infiltrated macrophages after ischemic stroke. In these transgenic mice, the chemokine receptor CX3CR1 is mainly expressed by brain-resident microglia, while CCR2 is overexpressed in infiltrating activated macrophages [5]. A profound characterization of these cell populations in damaged CNS may provide the opportunity to manipulate specific subsets for therapeutic benefits
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