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Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke.

Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B - Acta Neuropathol. (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsloewsvej 25, 5000, Odense C, Denmark. bclausen@health.sdu.dk.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of the presumed BM cell and microglial cross talk in the peri-infarct. The intravenously administered BM cells infiltrate the neural parenchyma in the peri-infarct where they ensure neuroprotection by interfering with the IL-1 self-promoting cycle, thereby stimulating subsets of microglia to secrete IL-1Ra. Infiltrating monocyte-derived macrophages and granulocytes produce insignificant amounts of IL-1Ra; however, macrophages are a major source of IL-1β. Note the heterogeneity of the microglia with some producing IL-1Ra and others producing IL-1β. A astrocyte; G: granulocytes; M: microglia; MФ macrophages; N neuron; O: oligodendrocyte; v vessel. Modified with permission from Dr. Ben Barres [2]
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Fig8: Schematic illustration of the presumed BM cell and microglial cross talk in the peri-infarct. The intravenously administered BM cells infiltrate the neural parenchyma in the peri-infarct where they ensure neuroprotection by interfering with the IL-1 self-promoting cycle, thereby stimulating subsets of microglia to secrete IL-1Ra. Infiltrating monocyte-derived macrophages and granulocytes produce insignificant amounts of IL-1Ra; however, macrophages are a major source of IL-1β. Note the heterogeneity of the microglia with some producing IL-1Ra and others producing IL-1β. A astrocyte; G: granulocytes; M: microglia; MФ macrophages; N neuron; O: oligodendrocyte; v vessel. Modified with permission from Dr. Ben Barres [2]

Mentions: The present study shows a novel function of therapeutically injected IL-1Ra-producing BM cells in stroke, as these cells enhance the production of anti-inflammatory IL-1Ra by microglia, collectively protecting the peri-infarct as demonstrated by reduced infarct volumes and improved functional outcome in mice. We show that IL-1Ra and IL-1β are expressed by segregated subsets of microglia, which, coupled with similar findings for TNF and IL-1β [10], supports the view of a functional heterogeneity among microglia [17, 18, 30, 51, 53]. As microglia react dynamically to changes, with input and feedback signals arising from cells within the peri-infarct which most likely affects their functional state, we suggest that microglial activation is not an “all-or-none” process in the brain. Antagonizing IL-1 is neuroprotective and our findings suggest that BM cells encoding the secreted form of (s)IL-1Ra under the control of its endogenous promoter may ensure neuroprotection by abrogating microglial/macrophage activation by interfering in the IL-1 self-promoting cycle toward neuroinflammation [20] (Fig. 8). Surprisingly, little is known about the production of IL-1Ra in situ and its neuroprotective role in the stroke-injured brain [43]. Although, a recent cross-laboratory study suggests that post-stroke peripheral administration of IL-1Ra is neuroprotective in mice [44], pharmacokinetic studies in patients have shown that rIL-1Ra crosses the blood brain barrier very slowly [28] and has a short half-life in the circulation [26], the challenge being to achieve therapeutic concentrations within the shortest time possible [24]. Although challenging to administer, the strength of a cell-based therapy is the ability of cells to actively infiltrate the neural parenchyma and modulate local inflammatory responses and neuronal survival in the tissue at risk over time.Fig. 8


Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke.

Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B - Acta Neuropathol. (2016)

Schematic illustration of the presumed BM cell and microglial cross talk in the peri-infarct. The intravenously administered BM cells infiltrate the neural parenchyma in the peri-infarct where they ensure neuroprotection by interfering with the IL-1 self-promoting cycle, thereby stimulating subsets of microglia to secrete IL-1Ra. Infiltrating monocyte-derived macrophages and granulocytes produce insignificant amounts of IL-1Ra; however, macrophages are a major source of IL-1β. Note the heterogeneity of the microglia with some producing IL-1Ra and others producing IL-1β. A astrocyte; G: granulocytes; M: microglia; MФ macrophages; N neuron; O: oligodendrocyte; v vessel. Modified with permission from Dr. Ben Barres [2]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835531&req=5

Fig8: Schematic illustration of the presumed BM cell and microglial cross talk in the peri-infarct. The intravenously administered BM cells infiltrate the neural parenchyma in the peri-infarct where they ensure neuroprotection by interfering with the IL-1 self-promoting cycle, thereby stimulating subsets of microglia to secrete IL-1Ra. Infiltrating monocyte-derived macrophages and granulocytes produce insignificant amounts of IL-1Ra; however, macrophages are a major source of IL-1β. Note the heterogeneity of the microglia with some producing IL-1Ra and others producing IL-1β. A astrocyte; G: granulocytes; M: microglia; MФ macrophages; N neuron; O: oligodendrocyte; v vessel. Modified with permission from Dr. Ben Barres [2]
Mentions: The present study shows a novel function of therapeutically injected IL-1Ra-producing BM cells in stroke, as these cells enhance the production of anti-inflammatory IL-1Ra by microglia, collectively protecting the peri-infarct as demonstrated by reduced infarct volumes and improved functional outcome in mice. We show that IL-1Ra and IL-1β are expressed by segregated subsets of microglia, which, coupled with similar findings for TNF and IL-1β [10], supports the view of a functional heterogeneity among microglia [17, 18, 30, 51, 53]. As microglia react dynamically to changes, with input and feedback signals arising from cells within the peri-infarct which most likely affects their functional state, we suggest that microglial activation is not an “all-or-none” process in the brain. Antagonizing IL-1 is neuroprotective and our findings suggest that BM cells encoding the secreted form of (s)IL-1Ra under the control of its endogenous promoter may ensure neuroprotection by abrogating microglial/macrophage activation by interfering in the IL-1 self-promoting cycle toward neuroinflammation [20] (Fig. 8). Surprisingly, little is known about the production of IL-1Ra in situ and its neuroprotective role in the stroke-injured brain [43]. Although, a recent cross-laboratory study suggests that post-stroke peripheral administration of IL-1Ra is neuroprotective in mice [44], pharmacokinetic studies in patients have shown that rIL-1Ra crosses the blood brain barrier very slowly [28] and has a short half-life in the circulation [26], the challenge being to achieve therapeutic concentrations within the shortest time possible [24]. Although challenging to administer, the strength of a cell-based therapy is the ability of cells to actively infiltrate the neural parenchyma and modulate local inflammatory responses and neuronal survival in the tissue at risk over time.Fig. 8

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsloewsvej 25, 5000, Odense C, Denmark. bclausen@health.sdu.dk.

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.

No MeSH data available.


Related in: MedlinePlus