Abstract
Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of IL-1Ra and IL-1α/β identifies microglia, not infiltrating leukocytes, as the major sources of IL-1Ra after experimental stroke, and shows IL-1Ra and IL-1β to be produced by segregated subsets of microglia with a small proportion of these cells co-expressing IL-1α. Reconstitution of whole body irradiated mice with IL-1Ra-producing bone marrow cells is associated with neuroprotection and recruitment of IL-1Ra-producing leukocytes after stroke. Neuroprotection is also achieved by therapeutic injection of IL-1Ra-producing bone marrow cells 30 min after stroke onset, additionally improving the functional outcome in two different stroke models. The IL-1Ra-producing bone marrow cells increase the number of IL-1Ra-producing microglia, reduce the availability of IL-1β, and modulate mitogen-activated protein kinase (MAPK) signaling in the ischemic cortex. The importance of these results is underlined by demonstration of IL-1Ra-producing cells in the human cortex early after ischemic stroke. Taken together, our results attribute distinct neuroprotective or neurotoxic functions to segregated subsets of microglia and suggest that treatment strategies increasing the production of IL-1Ra by infiltrating leukocytes or microglia may also be neuroprotective if applied early after stroke onset in patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1541-5) contains supplementary material, which is available to authorized users.
Highlights
Novel cell-based therapies have emerged during the past decade, with several ongoing trials investigating the therapeutic effect of bone marrow (BM) cells [48, 57], including mesenchymal stem cells [37], being a cellular source of interleukin-1 receptor antagonist (IL-1Ra) [50], which has anti-inflammatory effects [38] and neuroprotective functions in experimental stroke [43, 46, Acta Neuropathol (2016) 131:775–79152]
To obtain detailed insight into the cellular orchestration of IL-1Ra and IL-1(α/β), we examined the synthesis of all three cytokines in C57BL/6 mice after pMCAo
Within the peri-infarct, we found multiple process-bearing microglial-like cells with abundant IL-1Ra mRNA (Fig. 2b–d) and protein accumulation (Fig. 2f, g) 6, 12 and 24 h after pMCAo, and round vessel-associated leukocyte-like cells from 4 to 6 h after pMCAo
Summary
Novel cell-based therapies have emerged during the past decade, with several ongoing trials investigating the therapeutic effect of bone marrow (BM) cells [48, 57], including mesenchymal stem cells [37], being a cellular source of IL-1Ra [50], which has anti-inflammatory effects [38] and neuroprotective functions in experimental stroke [43, 46, Acta Neuropathol (2016) 131:775–79152]. An advantage of using cell-based therapies in stroke, next to or in combination with recanalization therapies [22], is that cells, which actively infiltrate the neural parenchyma at the site of injury [56, 59], may be able to modulate the inflammatory response in tissues at risk of being recruited into the expanding infarct. It is well documented that IL-1Ra attenuates the pro-inflammatory activities of IL-1(α/β) [6, 20, 39, 60, 61], key information about the cellular production of IL-1Ra and IL-1(α/β), and its orchestration in the tissue at risk in ischemic stroke is still lacking, but pivotal to the development of new therapeutic strategies
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